Co-crystals of SGLT2 inhibitors, process for their preparation and pharmaceutical compositions thereof

ABSTRACT

The present invention provides solid forms of SGLT2 inhibitors, to processes for their preparation and their use in the purification of SGLT2 inhibitors and also provided pharmaceutical compositions comprising them and their use in therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of and claims the benefit of the filingdate of U.S. patent application Ser. No. 15/759,562, filed on Mar. 13,2018, which is a national stage application of and claims the benefit ofInternational Application PCT/IB2016/055495, filed on Sep. 15, 2016,which is based on and claims the benefit of Indian ProvisionalApplication Nos. 4903/CHE/2015 filed on Sep. 15, 2015, entitled“Co-crystals of SGLT2 inhibitors, process for their preparation andpharmaceutical compositions thereof; IN201641010442 filed on Mar. 28,2016, entitled “Solid forms of dapagliflozin, process for itspreparation and pharmaceutical compositions thereof”; and IN201641029280filed on Aug. 29, 2016, entitled “Solid forms of empagliflozin, processfor its preparation and pharmaceutical compositions thereof”; thecontent of each of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to solid forms of SGLT1 inhibitors,processes for their preparation and use of such solid forms inpharmaceutical compositions and to their use in therapy. In particular,the present invention relates to solid forms of SGLT2 inhibitors,including their co-crystals, solvates and/or their polymorphs, processfor their preparation and a pharmaceutical composition comprising thesame.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a serious and chronic metabolic disease that ischaracterized by high blood glucose (hyperglycemia) and affects millionsof people worldwide. SGLT2 is a Sodium-dependent Glucose co-Transporterprotein, which affects the reabsorption of glucose in the kidney. It isestimated that 90% of renal glucose reabsorption is facilitated bySGLT2. Since glucose reabsorption is mediated predominantly by SGLT2 andbecause high glucose levels have been identified as a cause of diseasein diabetes, SGLT2 has become a drug target for type 2 diabetes therapy.Selective inhibition of SGLT2 has the potential to reduce hyperglycemiaby inhibiting glucose reabsorption in the kidney with elimination ofglucose by excretion in the urine (glucosuria).

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class ofdiabetic medications indicated only for the treatment of type 2diabetes. In conjunction with exercise and a healthy diet, they canimprove glycemic control. They have been studied alone and with othermedications including metformin, sulfonylureas, pioglitazone, DPP-4inhibitors and insulin.

Drugs in the SGLT2 inhibitors class include, but are not limited tocanagliflozin, dapagliflozin, empagliflozin and the like. The structuresof these SGLT2 inhibitors are represented below:

SGLT2 inhibitor compounds and their preparation process have beendescribed in the art, for example U.S. Pat. No. 7,943,788 disclosedcanagliflozin; U.S. Pat. No. 6,515,117 disclosed dapagliflozin and U.S.Pat. No. 7,579,449 disclosed empagliflozin.

Solid forms of SGLT2 inhibitor compounds in the form of crystallineforms, solvates, co-crystals, eutectic mixtures etc. have been describedin the art on various occasions, e.g. U.S. Pat. Nos. 6,774,112,7,723,309, 7,919,598, 7,943,582, 9,006,188, 9,035,044, WO 2002083066,WO2004063209, WO2007114475, WO2008002824, WO2013064909, WO2012163546,WO2013079501, WO2014178040, WO2015071761, WO2015132803, WO2015198227,WO2016018024, US2015307540, IN1985/MUM/2013, CN102167715B andCN103965267A.

Further, amorphous form of dapagliflozin has been described in the art,for example in U.S. Pat. No. 8,999,941; PCT Publication Nos. WO2015/104658, WO 2015/132803 and WO 2015/040571.

Obtaining suitable solid forms of a drug is a necessary stage for manyorally available drugs. Suitable solid forms possess the desiredproperties of a particular drug. Such suitable forms often possess morefavorable pharmaceutical and pharmacological properties or may be easierto process than known forms of the drug itself or may be used as a drugproduct intermediate during the preparation of the drug. For example,new drug formulations comprising crystalline forms of a given drug mayhave superior properties, such as solubility, dissolution,hygroscopicity and storage stability over existing formulations of thedrug.

Discovering new polymorphic forms, solvates or co-crystals of apharmaceutical product can provide materials having desirable processingproperties, such as ease of handling, ease of processing, storagestability, and ease of purification or as desirable intermediate formsthat facilitate conversion to other solid-state forms. New polymorphicforms, solvates or co-crystals of a pharmaceutically useful compound canalso provide an opportunity to improve the performance characteristicsof a pharmaceutical product. It enlarges the repertoire of materialsthat a formulation scientist has available for formulation optimization,for example by providing a product with different properties, e.g.,better processing or handling characteristics, better purity, improveddissolution profile, or improved shelf-life.

A co-crystal of a drug is a distinct chemical composition between thedrug and the co-crystal former, and generally possesses distinctcrystallographic and spectroscopic properties when compared to those ofthe drug and the co-crystal former individually. Unlike salts, whichpossess a neutral net charge, but which are comprised of charge-balancedcomponents, co-crystals are comprised of neutral species. Thus, unlike asalt, one cannot determine the stoichiometry of a co-crystal formerbased on charge balance. Indeed, one can often obtain co-crystals havingstoichiometric ratios of drug to the co-crystal former of greater thanor less than 1:1. The stoichiometric ratio of an API to co-crystalformer is a generally unpredictable feature of a co-crystal.

In view of the foregoing, it would be desirable to provide new solidforms of SGLT2 inhibitors. Further, it would be desirable to havereliable processes for producing these solid forms. Therefore, thepresent invention addresses the need in the art for pharmaceuticallyuseful solid forms of SGLT2 inhibitor that may have improvedphysicochemical properties, such as a higher solubility and dissolutionrate, enhanced flow properties and enhanced stability.

Although processes have been described in the art for the preparation ofamorphous dapagliflozin, there still remains a need for simple,environmental-friendly, stable, economical and industrially feasible andscalable processes for the preparation of dapagliflozin amorphous form.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides solid forms of SGLT2inhibitors, including its co-crystals, solvates and/or polymorphs,processes for their preparation, pharmaceutical compositions containingthe same and to their use in therapy.

In particular, the present invention relates to solid forms of SGLT2inhibitors, wherein the SGLT2 inhibitor can be, but is not limited tocanagliflozin, dapagliflozin, empagliflozin and the like, processes fortheir preparation and pharmaceutical compositions.

In accordance with another embodiment, the present invention providessolid forms of SGLT2 inhibitors, which are characterized by one or moreof analytical techniques such as powder X-Ray diffraction (XRD); ¹H NMRSpectrum; infrared spectrum (IR), differential scanning calorimetry(DSC) and/or thermogravimetric analysis (TGA), among others.

In accordance with one embodiment, the present invention provides novelco-crystals of SGLT2 inhibitors.

In accordance with another embodiment, the present invention providesthe solid forms of SGLT2 inhibitors exist in the form of co-crystals,solvates, polymorphs of co-crystals or polymorphs of solvates.

In accordance with another embodiment, the present invention providesco-crystals of SGLT2 inhibitors, wherein the SGLT2 inhibitor is selectedfrom canagliflozin, dapagliflozin, empagliflozin and the like.

In accordance with another embodiment, the present invention providesco-crystals of SGLT2 inhibitors and a co-crystal former, wherein theco-crystal former is selected from the group comprising DL-pipecolicacid, D-pipecolic acid, L-pipecolic acid, ammonia, nicotinic acid,isonicotinic acid, pyridine, pyrazole, pyrazine-2-carboxylic acid,imidazole, morpholine, proline and the like.

In accordance with another embodiment, the present invention providesco-crystals of SGLT2 inhibitors, wherein the SGLT2 inhibitor is selectedfrom canagliflozin, dapagliflozin, empagliflozin and the like andco-crystal former is selected from the group comprising DL-pipecolicacid, D-pipecolic acid, L-pipecolic acid, ammonia, nicotinic acid,isonicotinic acid, pyridine, pyrazole, pyrazine-2-carboxylic acid,imidazole, morpholine, proline and the like.

In accordance with another embodiment, the present invention provides aprocess for the preparation of co-crystals of SGLT2 inhibitors,comprising:

-   -   a) providing a solution or suspension comprising SGLT2 inhibitor        and a co-crystal former in one or more solvents; and    -   b) isolating the co-crystals of SGLT2 inhibitors; wherein the        SGLT2 inhibitor is selected from canagliflozin, dapagliflozin        and empagliflozin and wherein the co-crystal former is selected        from the group comprising DL-pipecolic acid, D-pipecolic acid,        L-pipecolic acid, ammonia, nicotinic acid, isonicotinic acid,        pyridine, pyrazole, pyrazine-2-carboxylic acid, imidazole,        morpholine, proline and the like.

In accordance with another embodiment, the present invention providesco-crystals of SGLT2 inhibitors, wherein the SGLT2 inhibitor isCanagliflozin.

In accordance with another embodiment, the present invention providesco-crystals of canagliflozin and a co-crystal former, wherein theco-crystal former is selected from the group comprising DL-pipecolicacid, D-pipecolic acid, L-pipecolic acid, ammonia, nicotinic acid,isonicotinic acid, pyridine, pyrazole, pyrazine-2-carboxylic acid,imidazole, morpholine and the like.

In accordance with another embodiment, the present invention providesco-crystal of canagliflozin and a co-crystal former, wherein theco-crystal former is selected from the group comprising DL-pipecolicacid, D-pipecolic acid, L-pipecolic acid, nicotinic acid, pyrazine2-carboxylic acid, ammonia or pyrazole.

In accordance with another embodiment, the present invention providescanagliflozin DL-pipecolic acid co-crystal.

In accordance with another embodiment, the present invention providescanagliflozin DL-pipecolic acid co-crystal characterized by X-Ray powderdiffraction (PXRD) pattern substantially in accordance with FIG. 01.

In accordance with another embodiment, the present invention providescanagliflozin DL-pipecolic acid co-crystal characterized by a ¹H NMRSpectrum substantially in accordance with FIG. 02.

In accordance with another embodiment, the present invention providescanagliflozin DL-pipecolic acid co-crystal characterized by adifferential scanning calorimetry (DSC) thermogram substantially inaccordance with FIG. 03.

In accordance with another embodiment, the present invention providescanagliflozin DL-pipecolic acid co-crystal characterized by athermogravimetric analysis (TGA) curve substantially in accordance withFIG. 04.

In accordance with another embodiment, the present invention providesCanagliflozin DL-pipecolic acid co-crystal characterized by an Infraredspectroscopy (IR) spectrum substantially in accordance with FIG. 05.

In accordance with another embodiment, the present invention providesCanagliflozin DL-pipecolic acid co-crystal characterized by one or moreof the following: a powder X-Ray diffraction (XRD) pattern substantiallyin accordance with FIG. 01; a ¹H NMR Spectrum substantially inaccordance with FIG. 02; a differential scanning calorimetry (DSC)thermogram substantially in accordance with FIG. 03; a thermogravimetricanalysis (TGA) curve substantially in accordance with FIG. 04 and/or anInfrared spectroscopy (IR) spectrum substantially in accordance withFIG. 05.

In accordance with another embodiment, the present invention provides aprocess for the preparation of Canagliflozin DL-pipecolic acidco-crystal, comprising providing a solution or suspension comprisingcanagliflozin and DL-pipecolic acid in one or more organic solvents andisolating the canagliflozin DL-pipecolic acid co-crystal.

In accordance with another embodiment, the present invention providescanagliflozin L-pipecolic acid co-crystal.

In accordance with another embodiment, the present invention provides aprocess for the preparation of Canagliflozin L-pipecolic acidco-crystal, comprising providing a solution or suspension comprisingcanagliflozin and L-pipecolic acid in one or more organic solvents andisolating the canagliflozin L-pipecolic acid co-crystal.

In accordance with another embodiment, the present invention providescanagliflozin D-pipecolic acid co-crystal.

In accordance with another embodiment, the present invention provides aprocess for the preparation of Canagliflozin D-pipecolic acidco-crystal, comprising providing a solution or suspension comprisingcanagliflozin and D-pipecolic acid in one or more organic solvents andisolating the canagliflozin D-pipecolic acid co-crystal.

In accordance with another embodiment, the present invention providescanagliflozin nicotinic acid co-crystal.

In accordance with another embodiment, the present invention provides aprocess for the preparation of Canagliflozin nicotinic acid co-crystal,comprising providing a solution or suspension comprising canagliflozinand nicotinic acid in one or more organic solvents and isolating thecanagliflozin nicotinic acid co-crystal.

In accordance with another embodiment, the present invention providescanagliflozin pyrazine-2-carboxylic acid co-crystal.

In accordance with another embodiment, the present invention provides aprocess for the preparation of Canagliflozin pyrazine-2-carboxylic acidco-crystal, comprising providing a solution or suspension comprisingcanagliflozin and pyrazine-2-carboxylic acid in one or more organicsolvents and isolating the canagliflozin pyrazine-2-carboxylic acidco-crystal.

In accordance with another embodiment, the present invention providescanagliflozin pyrazole co-crystal.

In accordance with another embodiment, the present invention provides aprocess for the preparation of Canagliflozin pyrazole co-crystal,comprising providing a solution or suspension comprising canagliflozinand pyrazole in one or more organic solvents and isolating thecanagliflozin pyrazole co-crystal.

In accordance with another embodiment, the solid forms of canagliflozinof the present invention may be used as an intermediate in obtaininghigh purity canagliflozin, preferably amorphous form of canagliflozin.

In accordance with another embodiment, the present invention provides animproved process for the preparation of canagliflozin from theco-crystals of canagliflozin of the present invention.

In accordance with another embodiment, the present invention provides animproved process for the preparation of canagliflozin, comprising:

-   -   a) preparing co-crystals of canagliflozin according to processes        described as above; and    -   b) converting the co-crystal of canagliflozin in to        canagliflozin.

In accordance with another embodiment, the present invention provides animproved process for the preparation of canagliflozin; comprising:

-   -   a) preparing co-crystal of canagliflozin according to processes        described as above; and    -   b) converting the co-crystal of canagliflozin in to        canagliflozin; wherein the co-crystal former is selected from        the group comprising DL-pipecolic acid, D-pipecolic acid,        L-pipecolic acid, ammonia, nicotinic acid, isonicotinic acid,        pyridine, pyrazole, pyrazine-2-carboxylic acid, imidazole,        morpholine and the like.

In accordance with another embodiment, the present invention providesco-crystals of dapagliflozin.

In accordance with another embodiment, the present invention providesco-crystals of dapagliflozin and a co-crystal former, wherein theco-crystal former is selected from the group comprising DL-pipecolicacid, D-pipecolic acid, L-pipecolic acid, ammonia, nicotinic acid,isonicotinic acid, pyridine, pyrazole, pyrazine-2-carboxylic acid,imidazole, morpholine, and the like.

In accordance with another embodiment, the present invention provides aprocess for the preparation of co-crystals of dapagliflozin, comprising:

-   -   a) providing a solution or suspension comprising dapagliflozin        and a co-crystal former in one or more organic solvents; and    -   b) isolating the co-crystals of dapagliflozin; wherein the        co-crystal former is selected from the group comprising        DL-pipecolic acid, D-pipecolic acid, L-pipecolic acid, ammonia,        nicotinic acid, isonicotinic acid, pyridine, pyrazole,        pyrazine-2-carboxylic acid, imidazole, morpholine, and the like.

In accordance with another embodiment, the present invention provides aprocess for the preparation of co-crystals of dapagliflozin, wherein theco-crystals are selected from the group comprising DL-pipecolic acid,D-pipecolic acid and L-pipecolic acid; comprising:

-   -   a) providing a solution or suspension comprising dapagliflozin        and a co-crystals former in one or more organic solvents; and    -   b) isolating the co-crystals of dapagliflozin, wherein the        co-crystals former is selected from the group comprising        DL-pipecolic acid, D-pipecolic acid and L-pipecolic acid.

In accordance with another embodiment, the present invention providesco-crystals of dapagliflozin and a co-crystal former, wherein theco-crystal former is selected from the group comprising DL-pipecolicacid, D-pipecolic acid or L-pipecolic acid.

In accordance with another embodiment, the present invention providesdapagliflozin DL-pipecolic acid co-crystals.

In accordance with another embodiment, the present invention providesdapagliflozin DL-pipecolic acid co-crystals characterized by X-Raypowder diffraction (XRD) pattern substantially in accordance with FIG.09.

In accordance with another embodiment, the present invention providesdapagliflozin DL-pipecolic acid co-crystals characterized by a ¹H NMRSpectrum substantially in accordance with FIG. 10.

In accordance with another embodiment, the present invention providesdapagliflozin DL-pipecolic acid co-crystals characterized by adifferential scanning calorimetry (DSC) thermogram substantially inaccordance with FIG. 11.

In accordance with another embodiment, the present invention providesdapagliflozin DL-pipecolic acid co-crystals characterized by athermogravimetric analysis (TGA) curve substantially in accordance withFIG. 12.

In accordance with another embodiment, the present invention providesdapagliflozin DL-pipecolic acid co-crystals characterized by one or moreof the following: a powder X-Ray diffraction (XRD) pattern substantiallyin accordance with FIG. 09; a ¹H NMR Spectrum substantially inaccordance with FIG. 10; a differential scanning calorimetry (DSC)thermogram substantially in accordance with FIG. 11; and/or athermogravimetric analysis (TGA) curve substantially in accordance withFIG. 12.

In accordance with another embodiment, the present invention provides aprocess for the preparation of dapagliflozin DL-pipecolic acidco-crystals, comprising providing a solution or suspension comprisingdapagliflozin and DL-pipecolic acid in one or more organic solvents andisolating the dapagliflozin DL-pipecolic acid co-crystals.

In accordance with another embodiment, the present invention providesdapagliflozin D-pipecolic acid co-crystals.

In accordance with another embodiment, the present invention providesdapagliflozin D-pipecolic acid co-crystals characterized by X-Ray powderdiffraction (XRD) pattern substantially in accordance with FIG. 13.

In accordance with another embodiment, the present invention provides aprocess for the preparation of dapagliflozin D-pipecolic acidco-crystals, comprising providing a solution or suspension comprisingdapagliflozin and D-pipecolic acid in one or more organic solvents andisolating the dapagliflozin D-pipecolic acid co-crystals.

In accordance with another embodiment, the present invention providesdapagliflozin L-pipecolic acid co-crystals.

In accordance with another embodiment, the present invention providesdapagliflozin L-pipecolic acid co-crystals characterized by X-Ray powderdiffraction (XRD) pattern substantially in accordance with FIG. 14.

In accordance with another embodiment, the present invention provides aprocess for the preparation of dapagliflozin L-pipecolic acidco-crystals, comprising providing a solution or suspension comprisingdapagliflozin and L-pipecolic acid in one or more organic solvents andisolating the dapagliflozin L-pipecolic acid co-crystals.

In accordance with another embodiment, the present invention providesdapagliflozin 2,3-butanediol solvate.

In accordance with another embodiment, the present invention providescrystalline dapagliflozin 2,3-butanediol solvate.

In accordance with another embodiment, the present invention providescrystalline dapagliflozin 2,3-butanediol solvate characterized by X-Raypowder diffraction (XRD) pattern substantially in accordance with FIG.15.

In accordance with another embodiment, the present invention providescrystalline dapagliflozin 2,3-butanediol solvate characterized by a ¹HNMR Spectrum substantially in accordance with FIG. 16.

In accordance with another embodiment, the present invention providescrystalline dapagliflozin 2,3-butanediol solvate characterized by adifferential scanning calorimetry (DSC) thermogram substantially inaccordance with FIG. 17.

In accordance with another embodiment, the present invention providescrystalline dapagliflozin 2,3-butanediol solvate characterized by athermogravimetric analysis (TGA) curve substantially in accordance withFIG. 18.

In accordance with another embodiment, the present invention providesdapagliflozin 2,3-butanediol solvate characterized by one or more of thefollowing: a powder X-Ray diffraction (XRD) pattern substantially inaccordance with FIG. 15; a ¹H NMR Spectrum substantially in accordancewith FIG. 16; a differential scanning calorimetry (DSC) thermogramsubstantially in accordance with FIG. 17; and/or a thermogravimetricanalysis (TGA) curve substantially in accordance with FIG. 18.

In accordance with another embodiment, the present invention provides aprocess for the preparation of dapagliflozin 2,3-butanediol solvate,comprising:

-   -   a) dissolving dapagliflozin or a solvate or a co-crystal in an        organic solvent,    -   b) treating the above solution with 2,3-butanediol,    -   c) optionally adding seed crystals of dapagliflozin        2,3-butanediol solvate,    -   d) adding an anti-solvent to the reaction mass, and    -   e) isolating the dapagliflozin 2,3-butanediol solvate.

In accordance with another embodiment, the solid forms of dapagliflozinof the present invention may be used as an intermediate in obtaininghigh purity dapagliflozin, preferably amorphous form of dapagliflozin.

In accordance with another embodiment, the present invention provides aprocess for the preparation of amorphous form of dapagliflozin, whereinthe process involves one or more solid forms of dapagliflozin of theinvention as an intermediate.

In accordance with another embodiment, the present invention provides aprocess for the preparation of amorphous dapagliflozin, comprising:

-   -   a) dissolving or suspending dapagliflozin co-crystals in a        suitable solvent;    -   b) optionally treating the step a) reaction mass with a suitable        base or an acid;    -   c) extracting dapagliflozin into an organic solvent; and    -   d) removing the solvent to obtain amorphous form of        dapagliflozin.

In accordance with another embodiment, the present invention provides aprocess for the preparation of amorphous dapagliflozin, comprising:

-   -   a) dissolving or suspending dapagliflozin co-crystals in a        suitable solvent,    -   b) treating the step a) reaction mass with a suitable base or an        acid,    -   c) optionally extracting dapagliflozin into an organic solvent,    -   d) removing the solvent to obtain a residue,    -   e) dissolving the residue in an organic solvent to obtain a        solution,    -   f) adding an anti-solvent to the step e) solution or vice-versa,    -   g) optionally seeding with amorphous dapagliflozin, and    -   h) isolating the amorphous dapagliflozin.

In accordance with another embodiment, the present invention provides aprocess for the preparation of amorphous dapagliflozin, comprising:

-   -   a) providing a solution of dapagliflozin in a solvent selected        from the group consisting of esters, ethers, alcohols, ketones,        nitriles or mixtures thereof, and    -   b) removing the solvent from the solution to obtain amorphous        form of dapagliflozin.

In accordance with another embodiment, the present invention provides aprocess for the preparation of amorphous dapagliflozin, comprising:

-   -   a) providing a solution of dapagliflozin in a solvent selected        from the group consisting of esters, ethers, alcohols, ketones,        nitriles or mixtures thereof,    -   b) adding an anti-solvent to the solution or vice versa,    -   c) optionally seeding with amorphous dapagliflozin, and    -   d) isolating the amorphous form of dapagliflozin; wherein the        anti-solvent is selected from the group consisting of water,        hydrocarbons solvents, ether solvents or mixtures thereof.

In accordance with another embodiment, the present invention providesco-crystals of empagliflozin.

In accordance with another embodiment, the present invention providesco-crystals of Empagliflozin and a co-crystal former, wherein theco-crystal former is selected from the group comprising DL-pipecolicacid, D-pipecolic acid, L-pipecolic acid, ammonia, nicotinic acid,isonicotinic acid, pyridine, pyrazole, pyrazine-2-carboxylic acid,imidazole, morpholine, proline and the like.

In accordance with another embodiment, the present invention provides aprocess for the preparation of co-crystals of empagliflozin, comprising:

-   -   a) providing a solution or suspension comprising empagliflozin        and a co-crystal former,    -   b) isolating the co-crystals of empagliflozin; wherein the        co-crystal former is selected from the group comprising        DL-pipecolic acid, D-pipecolic acid, L-pipecolic acid, ammonia,        nicotinic acid, isonicotinic acid, pyridine, pyrazole,        pyrazine-2-carboxylic acid, imidazole, morpholine, proline and        the like.

In accordance with another embodiment, the present invention providesempagliflozin DL-pipecolic acid co-crystals.

In accordance with another embodiment, the present invention providesempagliflozin DL-pipecolic acid co-crystals hydrate.

In accordance with another embodiment, the present invention providesempagliflozin DL-pipecolic acid co-crystals characterized by X-Raypowder diffraction (XRD) pattern substantially in accordance with FIG.21.

In accordance with another embodiment, the present invention providesempagliflozin DL-pipecolic acid co-crystals characterized by ¹H NMRSpectrum substantially in accordance with FIG. 22.

In accordance with another embodiment, the present inventionempagliflozin DL-pipecolic acid co-crystals characterized by adifferential scanning calorimetry (DSC) thermogram substantially inaccordance with FIG. 23.

In accordance with another embodiment, the present invention providesempagliflozin DL-pipecolic acid co-crystals characterized by athermogravimetric analysis (TGA) curve substantially in accordance withFIG. 24.

In accordance with another embodiment, the present invention providesempagliflozin DL-pipecolic acid co-crystals characterized by one or moreof the following: a powder X-Ray diffraction (XRD) pattern substantiallyin accordance with FIG. 21; a ¹H NMR Spectrum substantially inaccordance with FIG. 22; a differential scanning calorimetry (DSC)thermogram substantially in accordance with FIG. 23; and/or athermogravimetric analysis (TGA) curve substantially in accordance withFIG. 24.

In accordance with another embodiment, the present invention provides aprocess for the preparation of empagliflozin DL-pipecolic acidco-crystals, comprising:

-   -   a) providing a solution or suspension comprising empagliflozin        and DL-pipecolic acid, and    -   b) isolating the empagliflozin DL-pipecolic acid co-crystals.

In accordance with another embodiment, the solid forms of co-crystals ofempagliflozin of the present invention may be used as an intermediate inobtaining high purity empagliflozin.

In accordance with another embodiment, the present invention providessolid forms of SGLT2 inhibitors, which may have greater stability,bioavailability, and having desired pharmacological, pharmacokinetic andpharmacodynamic effects.

In accordance with another embodiment, the present invention provides apharmaceutical composition comprising at least one of the solid forms ofSGLT2 inhibitors described above and at least one or morepharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate several embodiments of theinvention and together with the description, serve to explain theprinciples of the invention.

FIG. 1 is the characteristic powder XRD pattern of CanagliflozinDL-pipecolic acid co-crystal.

FIG. 2 is the characteristic ¹H NMR Spectrum of CanagliflozinDL-pipecolic acid co-crystal.

FIG. 3 is the characteristic DSC thermogram of CanagliflozinDL-pipecolic acid co-crystal.

FIG. 4 is the characteristic TGA curve of Canagliflozin DL-pipecolicacid co-crystal.

FIG. 5 is the characteristic IR spectrum of Canagliflozin DL-pipecolicacid co-crystal.

FIG. 6 is the characteristic powder XRD pattern of Canagliflozinobtained according to example 10 of the present invention.

FIG. 7 is the characteristic TGA curve of Canagliflozin obtainedaccording to example 10 of the present invention.

FIG. 8 is the characteristic IR spectrum of Canagliflozin obtainedaccording to example 10 of the present invention.

FIG. 9 is the characteristic powder XRD pattern of dapagliflozinDL-pipecolic acid co-crystal.

FIG. 10 is the characteristic ¹H NMR Spectrum of dapagliflozinDL-pipecolic acid co-crystals.

FIG. 11 is the characteristic DSC thermogram of dapagliflozinDL-pipecolic acid co-crystals.

FIG. 12 is the characteristic TGA curve of dapagliflozin DL-pipecolicacid co-crystal.

FIG. 13 is the characteristic powder XRD pattern of dapagliflozinD-pipecolic acid co-crystals.

FIG. 14 is the characteristic powder XRD pattern of dapagliflozinL-pipecolic acid co-crystals.

FIG. 15 is the characteristic powder XRD pattern of dapagliflozin2,3-butanediol solvate.

FIG. 16 is the characteristic ¹H NMR Spectrum of dapagliflozin2,3-butanediol solvate.

FIG. 17 is the characteristic DSC thermogram of dapagliflozin2,3-butanediol solvate.

FIG. 18 is the characteristic TGA curve of dapagliflozin 2,3-butanediolsolvate.

FIG. 19 is the characteristic powder XRD pattern of amorphousdapagliflozin.

FIG. 20 is the characteristic DSC thermogram of amorphous dapagliflozin.

FIG. 21 is the characteristic powder XRD pattern of empagliflozinDL-pipecolic acid co-crystals.

FIG. 22 is the characteristic ¹H NMR Spectrum of empagliflozinDL-pipecolic acid co-crystals.

FIG. 23 is the characteristic DSC thermogram of empagliflozinDL-pipecolic acid co-crystals.

FIG. 24 is the characteristic TGA curve of empagliflozin DL-pipecolicacid co-crystals.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “co-crystals” means a crystalline materialcomprised of two or more unique solids at room temperature, eachcontaining distinctive physical characteristics, such as structure,melting point and heats of fusion.

As used herein, the term “solvate” refers to a crystalline compound inwhich molecules of solvents are incorporated into the crystal lattice ofthe compound.

The starting SGLT2 inhibitors used in the present invention is known inthe art and can be prepared by any known methods, for exampleCanagliflozin may be synthesized as disclosed in U.S. Pat. Nos.7,943,788 and 9,024,009; Dapagliflozin may be synthesized as disclosedin U.S. Pat. Nos. 6,515,117, 7,375,213, 7,932,379 and 7,919,598; andEmpagliflozin may be synthesized as disclosed in U.S. Pat. No.7,579,449, which are incorporated herein by reference; or the SGLT2inhibitor may be obtained as a solution directly from a reaction mixturein which it is formed and used as such without isolation.

The present invention relates to solid forms of SGLT2 inhibitors,including their co-crystals, solvates and/or their polymorphs, processesfor their preparation, pharmaceutical compositions containing the sameand to their use in therapy.

In accordance with another embodiment, the present invention providesthe solid forms of SGLT2 inhibitors exist in the form of co-crystals,solvates, polymorphs of co-crystals or polymorphs of solvates.

In particular, the present invention relates to solid forms of SGLT2inhibitors, wherein the SGLT2 inhibitor can be, but is not limited toCanagliflozin, Dapagliflozin, Empagliflozin and the like, processes fortheir preparation and pharmaceutical compositions.

In accordance with one embodiment, the present invention provides novelco-crystals of SGLT2 inhibitors.

In accordance with another embodiment, the present invention providesco-crystals of SGLT2 inhibitors, wherein the SGLT2 inhibitor is selectedfrom Canagliflozin, Dapagliflozin, Empagliflozin and the like.

In accordance with another embodiment, the present invention providesco-crystals of SGLT2 inhibitors and a co-crystal former, wherein theco-crystal former is selected from the group comprising DL-pipecolicacid, D-pipecolic acid, L-pipecolic acid, ammonia, nicotinic acid,isonicotinic acid, pyridine, pyrazole, pyrazine-2-carboxylic acid,imidazole, morpholine, proline and the like.

In accordance with another embodiment, the present invention providesco-crystals of SGLT2 inhibitors, wherein the SGLT2 inhibitor is selectedfrom the group comprising Canagliflozin, Dapagliflozin, Empagliflozinand the like and co-crystal former is selected from the group comprisingDL-pipecolic acid, D-pipecolic acid, L-pipecolic acid, ammonia,nicotinic acid, isonicotinic acid, pyridine, pyrazole,pyrazine-2-carboxylic acid, imidazole, morpholine, proline and the like.

The ratio of SGLT2 inhibitor to co-crystal former may be stoichiometricor non-stoichiometric according to the present invention. For example,1:1, 1.5:1, 1:1.5, 2:1 and 1:2 ratios of SGLT2 inhibitor:co-crystalformer is acceptable.

In accordance with another embodiment, the present invention providesco-crystals of SGLT2 inhibitors, which are characterized by one or moreof analytical techniques such as powder X-Ray diffraction (XRD); ¹H NMRSpectrum; infrared spectrum (IR), differential scanning calorimetry(DSC) and/or thermogravimetric analysis (TGA), among others.

In accordance with another embodiment, the present invention provides aprocess for the preparation of co-crystals of SGLT2 inhibitors,comprising:

-   -   a) providing a solution or suspension comprising SGLT2 inhibitor        and a co-crystal former in one or more solvents; and    -   b) isolating the co-crystals of SGLT2 inhibitors; wherein the        SGLT2 inhibitor is selected from the group comprising        Canagliflozin, Dapagliflozin and Empagliflozin and wherein the        co-crystal former is selected from the group comprising        DL-pipecolic acid, D-pipecolic acid, L-pipecolic acid, ammonia,        nicotinic acid, isonicotinic acid, pyridine, pyrazole,        pyrazine-2-carboxylic acid, imidazole, morpholine, proline and        the like.

The step of providing a solution or suspension includes any form ofSGLT2 inhibitor that may be combined with one or more organic solventsat a suitable temperature, and then the co-crystal former may be mixedwith the resulting solution or slurry. Alternatively, the mixture may beformed by adding both the SGLT2 inhibitor and the co-crystal former atthe same time in to one or more organic solvents.

Suitable one or more solvents includes but are not limited to alcohols,esters, ethers, ketones, nitriles, halogenated hydrocarbons, aromatichydrocarbons, aliphatic hydrocarbons, amides, nitroalkanes and the like;water and mixtures thereof.

The alcohols include, but are not limited to methanol, ethanol,isopropanol, n-propanol, n-butanol, isobutanol and the like; estersinclude, but are not limited to methyl acetate, ethyl acetate, isopropylacetate and the like; ethers include, but are not limited totetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiarybutyl ether, 1,4-dioxane and the like; ketones include, but are notlimited to acetone, methyl isobutyl ketone, methyl ethyl ketone and thelike; nitriles include, but are not limited to acetonitrile,propionitrile and the like; halogenated hydrocarbons include, but arenot limited to methylene chloride, ethylene chloride, chloroform, carbontetrachloride and the like; aromatic hydrocarbons include, but are notlimited to toluene, xylene and the like; aliphatic hydrocarbons include,but are not limited to n-hexane, n-heptane, cyclohexane and the like;amides include, but are not limited to dimethyl formamide, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidinone and the like;nitroalkanes include, but are not limited to nitromethane, nitroethaneand the like and mixtures thereof. Preferably the one or more solventsinclude methanol, ethanol, n-butanol, ethyl acetate, isopropyl acetate,hexane, heptane and mixtures thereof; more preferably ethanol,n-butanol, ethyl acetate, isopropyl acetate, heptane and mixturesthereof and optionally a mixture of these solvents with water.

The temperature suitable for dissolving or suspending the SGLT2inhibitor in the one or more organic solvents depends on the solventused and the amount of SGLT2 inhibitor in the reaction mass. Typically,the solution or suspension is heated at a temperature of at least about30° C. to about reflux.

In step b) of the foregoing process, the isolation of co-crystals ofSGLT2 inhibitors may be carried out by crystallization, solventprecipitation, concentration by subjecting the solution to heating,spray drying, freeze drying, evaporation on rotary evaporator undervacuum, agitated thin film evaporator (ATFE) and the like. Preferably,the reaction may be cooled to a temperature from about 35° C. or lessand then an antisolvent such as n-heptane is added and then optionallythe reaction medium can be heated to about 40° C. to about 75° andfollowed by cooling the suspension to less than about 30° C. Theprecipitated product can be recovered by conventional techniques, forexample filtration.

The obtained co-crystal of SGLT2 inhibitor, if required, is furtherpurified by heating the co-crystal of SGLT2 inhibitor in a suitableorganic solvent selected from the group consisting of alcohols, esters,ketones, ethers, halogenated solvents, hydrocarbons, nitriles,carbonates, nitro alkanes, glycols, water or mixtures thereof.

Examples of suitable organic solvent for purifying co-crystals of thepresent invention include but are not limited to alcohols such asmethanol, ethanol, isopropanol, n-butanol, sec-butanol, tert-butanol,and the like; esters such as ethyl acetate, isopropyl acetate, n-butylacetate, isobutyl acetate, tert-butyl acetate and the like; ketones suchas acetone, methyl isobutyl ketone, 2-pentanone, cyclopentanone,cyclohexanone and the like; ethers such as diisopropyl ether, ditert-butyl ether, ethyl tert-butyl ether, and the like; halogenatedsolvents such as dichloromethane, 1-chlorobutane, and the like;hydrocarbons such as hexane, heptane, pentane, cyclohexane, methylcyclohexane, and the like; nitriles such as acetonitrile, propionitrile,butyronitrile, benzonitrile and the like; carbonates such as diethylcarbonate, propylene carbonate, dibenzyl carbonate and the like; nitroalkanes such as nitromethane, nitroethane and the like; glycols such asethylene glycol, propylene glycol and the like; water or mixturesthereof. Preferably the suitable organic solvent includes methanol,ethanol, isopropyl acetate, ethyl acetate, acetone and mixtures thereof;more preferably ethanol, ethyl acetate and mixtures thereof.

The mixture of co-crystal of SGLT2 inhibitor and the suitable organicsolvent may be heated to dissolve all solids in to solvent at atemperature of about 30° C. to reflux. Then the resultant solution mayoptionally be cooled to less than 30° C. and the precipitated solid canbe isolated by conventional techniques known in the art, for example,filtration. The resultant co-crystals of SGLT2 inhibitors may optionallybe further dried. Drying can be suitably carried out in a tray dryer,vacuum oven, air oven, fluidized bed drier, spin flash dryer, flashdryer and the like. The drying can be carried out at a temperatureranging from about 40° C. to about 100° C.

In another embodiment, the present invention provides co-crystals ofSGLT2 inhibitors having a chemical purity greater than or equal to about97%, as measured by HPLC, preferably about 98% as measured by HPLC, andmore preferably about 99.5%, as measured by HPLC.

In another embodiment, the co-crystals of the present invention areobtained in substantially pure form.

Furthermore, some of the co-crystals of the present invention may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the co-crystals of the present inventionmay form solvates with water (i.e., hydrates) or common organicsolvents, and such solvates are also intended to be encompassed withinthe scope of this invention.

In another embodiment, the present invention provides co-crystals ofSGLT2 inhibitors, wherein the SGLT2 inhibitor is Canagliflozin.

In another embodiment, the present invention provides co-crystals ofCanagliflozin and a co-crystal former, where in the co-crystal former isselected from the group comprising DL-pipecolic acid, D-pipecolic acid,L-pipecolic acid, ammonia, nicotinic acid, isonicotinic acid, pyridine,pyrazole, pyrazine-2-carboxylic acid, imidazole, morpholine and thelike.

In another embodiment, the present invention provides co-crystals ofcanagliflozin and a co-crystal former, wherein the co-crystal former isselected from the group comprising DL-pipecolic acid, D-pipecolic acid,L-pipecolic acid, nicotinic acid, pyrazine 2-carboxylic acid, ammonia orpyrazole.

In another embodiment, the present invention provides CanagliflozinDL-pipecolic acid co-crystals.

In another embodiment, the present invention provides a process for thepreparation of Canagliflozin DL-pipecolic acid co-crystals, comprisingproviding a solution or suspension comprising Canagliflozin andDL-pipecolic acid in one or more organic solvents and isolating theCanagliflozin DL-pipecolic acid co-crystal.

Examples of one or more organic solvents used herein in the foregoingprocess includes but are not limited to alcohols such as methanol,ethanol, n-propanol, isopropanol, n-butanol, iso-butanol and the like;ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone andthe like; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran,diethyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like;aliphatic hydrocarbons such as hexane, heptane, pentane and the like;aromatic hydrocarbons such as toluene, xylene and the like; halogenatedhydrocarbons such as dichloromethane, chloroform and the like; nitrilessuch as acetonitrile, propionitrile, benzonitrile and the like ormixtures thereof. Preferably the one or more organic solvents includemethanol, ethanol, n-butanol, ethyl acetate, isopropyl acetate, hexane,heptane and mixtures thereof; more preferably ethanol, n-butanol, ethylacetate, isopropyl acetate, heptane and mixtures thereof and optionallya mixture of these solvents with water.

The step of providing a solution or suspension comprising Canagliflozinand DL-pipecolic acid in organic solvent may include heating to dissolveCanagliflozin and DL-pipecolic acid in the organic solvent. Thetemperature suitable for dissolving or suspending the Canagliflozin andDL-pipecolic acid in the organic solvent depends on the solvent used andthe amount of Canagliflozin and DL-pipecolic acid in the solution.Typically, it is heated at a temperature of at least about 30° C. toabout reflux. Preferably, the solution is heated at about 30° C. toabout 80° C.

Isolation of the Canagliflozin DL-pipecolic acid co-crystal obtained maybe carried out by optionally allowing the reaction mass to graduallycool to a temperature of less than 30° C. and the CanagliflozinDL-pipecolic acid co-crystal can be isolated by conventional techniques,for example by filtration.

The obtained Canagliflozin DL-pipecolic acid co-crystal, if required, isfurther purified by heating the co-crystal of SGLT2 inhibitor in asuitable organic solvent selected from the group consisting of alcohols,esters, ketones, ethers, halogenated solvents, hydrocarbons, nitriles,carbonates, alkyl nitrates, glycols, water or mixtures thereof.

Examples of suitable organic solvent for purifying CanagliflozinDL-pipecolic acid co-crystal is represented as solvents mentioned justas above for the purification step of SGL2 inhibitors. Preferably thesuitable organic solvent for purification of Canagliflozin DL-pipecolicacid co-crystal includes methanol, ethanol, isopropyl acetate, ethylacetate, acetone and mixtures thereof; more preferably ethanol, ethylacetate and mixtures thereof.

The mixture of Canagliflozin DL-pipecolic acid co-crystal and thesuitable organic solvent may be heated to dissolve all solids in tosolvent at a temperature of about 30° C. to reflux. Then the resultantsolution may optionally be cooled to less than 30° C. and theprecipitated solid can be isolated by conventional techniques known inthe art, for example, filtration. The resultant CanagliflozinDL-pipecolic acid co-crystal may optionally be further dried. Drying canbe suitably carried out in a tray dryer, vacuum oven, air oven,fluidized bed drier, spin flash dryer, flash dryer and the like. Thedrying can be carried out at a temperature ranging from about 40° C. toabout 100° C., preferably from about 50° C. to about 80° C.

In another embodiment, Canagliflozin DL-pipecolic acid co-crystalrecovered using the process as described just above is substantially acrystalline form.

In another embodiment, the present invention provides CanagliflozinDL-pipecolic acid co-crystal characterized by X-Ray powder diffraction(XRD) pattern substantially in accordance with FIG. 01.

In another embodiment, the present invention provides CanagliflozinDL-pipecolic acid co-crystal characterized by X-Ray powder diffraction(XRD) pattern having one or more peaks at about 4.00, 9.12, 9.60, 10.50,11.34, 14.92, 17.56, 17.92, 18.92, 19.80, 20.18, 20.60, 21.74, 22.20,22.94, 23.48 and 26.90±0.2° 20.

In another embodiment, the present invention provides CanagliflozinDL-pipecolic acid co-crystal characterized by a ¹H NMR Spectrumsubstantially in accordance with FIG. 02.

In another embodiment, the present invention provides CanagliflozinDL-pipecolic acid co-crystal characterized by a differential scanningcalorimetry (DSC) thermogram substantially in accordance with FIG. 03.

In another embodiment, the present invention provides CanagliflozinDL-pipecolic acid co-crystal characterized by a thermogravimetricanalysis (TGA) curve substantially in accordance with FIG. 04.

In another embodiment, the present invention provides CanagliflozinDL-pipecolic acid co-crystal characterized by an Infrared spectroscopy(IR) spectrum substantially in accordance with FIG. 05.

In another embodiment, the present invention provides CanagliflozinDL-pipecolic acid co-crystal characterized by one or more of thefollowing: a powder X-Ray diffraction (XRD) pattern substantially inaccordance with FIG. 01; a ¹H NMR Spectrum substantially in accordancewith FIG. 02; a differential scanning calorimetry (DSC) thermogramsubstantially in accordance with FIG. 03; a thermogravimetric analysis(TGA) curve substantially in accordance with FIG. 04 and/or an Infraredspectroscopy (IR) spectra substantially in accordance with FIG. 05.

In another embodiment, the present invention provides canagliflozinL-pipecolic acid co-crystal.

In another embodiment, the present invention provides a process for thepreparation of Canagliflozin L-pipecolic acid co-crystal, comprisingproviding a solution or suspension comprising canagliflozin andL-pipecolic acid in one or more organic solvents and isolating thecanagliflozin L-pipecolic acid co-crystal.

The aforementioned process for the preparation of canagliflozinL-pipecolic acid co-crystal includes dissolving canagliflozin andL-pipecolic acid in one or more organic solvents as herein beforedefined; preferably ethanol, ethyl acetate and mixtures thereof at asuitable temperature, for example at about 30° C. to about refluxtemperature, preferably at about 50° C. to reflux. Then cooling thereaction mixture to less than 60° C. and then optionally an antisolventsuch as n-heptane may be added to precipitation of the resultant productor directly cooling the reaction solution to precipitation. Theprecipitated Canagliflozin L-pipecolic acid co-crystal can be recoveredby conventional techniques, for example filtration.

Optionally, the resultant Canagliflozin L-pipecolic acid co-crystals maybe purified using a suitable solvent system. Preferable solventincludes, but are not limited to ethanol, ethyl acetate and mixturesthereof. The mixture of Canagliflozin L-pipecolic acid co-crystal andthe suitable organic solvent may be heated to dissolve all solids in tosolvent at a temperature of about 30° C. to reflux. Then the resultantsolution may optionally be cooled to less than 30° C. and theprecipitated solid can be isolated by conventional techniques known inthe art, for example, filtration followed by optionally dried.

In another embodiment, the present invention provides canagliflozinD-pipecolic acid co-crystal.

In another embodiment, the present invention provides a process for thepreparation of Canagliflozin D-pipecolic acid co-crystal, comprisingproviding a solution or suspension comprising canagliflozin andD-pipecolic acid in one or more organic solvents and isolating thecanagliflozin D-pipecolic acid co-crystal.

The aforementioned process for the preparation of canagliflozinD-pipecolic acid co-crystal includes dissolving canagliflozin andD-pipecolic acid in one or more organic solvents as herein beforedefined; preferably ethanol, ethyl acetate and mixtures thereof at asuitable temperature, for example at about 30° C. to about refluxtemperature, preferably at about 50° C. to reflux. Then cooling thereaction mixture to less than 60° C. and then optionally an antisolventsuch as n-heptane may be added to precipitation of the resultant productor directly cooling the reaction solution to precipitation. Theprecipitated Canagliflozin D-pipecolic acid co-crystal can be recoveredby conventional techniques, for example filtration.

Optionally, the resultant Canagliflozin D-pipecolic acid co-crystals maybe purified using a suitable solvent system. Preferable solventincludes, but are not limited to ethanol, ethyl acetate and mixturesthereof. The mixture of Canagliflozin D-pipecolic acid co-crystal andthe suitable organic solvent may be heated to dissolve all solids in tosolvent at a temperature of about 30° C. to reflux. Then the resultantsolution may optionally be cooled to less than 30° C. and theprecipitated solid can be isolated by conventional techniques known inthe art, for example, filtration followed by optionally dried.

In another embodiment, the present invention provides canagliflozinnicotinic acid co-crystal.

In another embodiment, the present invention provides a process for thepreparation of Canagliflozin nicotinic acid co-crystal, comprisingproviding a solution or suspension comprising canagliflozin andnicotinic acid in one or more organic solvents and isolating thecanagliflozin nicotinic acid co-crystal.

The above mentioned process for the preparation of canagliflozinnicotinic acid co-crystal includes dissolving canagliflozin andnicotinic acid in one or more organic solvents as herein before defined;preferably in ethanol at a suitable temperature, for example at about30° C. to about reflux temperature, preferably at about 50° C. to aboutreflux temperature. Then cooling the reaction mixture to less than about30° C. and isolating the resulting Canagliflozin nicotinic acidco-crystal by conventional techniques, for example by filtration.

In another embodiment, the present invention provides canagliflozinpyrazine-2-carboxylic acid co-crystal.

In another embodiment, the present invention provides a process for thepreparation of Canagliflozin pyrazine-2-carboxylic acid co-crystal,comprising providing a solution or suspension comprising canagliflozinand pyrazine-2-carboxylic acid in one or more organic solvents andisolating the canagliflozin pyrazine-2-carboxylic acid co-crystal.

The above mentioned process for the preparation of canagliflozinpyrazine-2-carboxylic acid co-crystal includes dissolving canagliflozinand pyrazine-2-carboxylic acid in one or more organic solvents as hereinbefore defined; preferably in ethanol at a suitable temperature, forexample at about 30° C. to about reflux temperature, preferably at about50° C. to about reflux temperature. Then cooling the reaction mixture toroom temperature and isolating the resulting Canagliflozinpyrazine-2-carboxylic acid co-crystal by conventional techniques, forexample by filtration.

In another embodiment, the present invention provides canagliflozinpyrazole co-crystal.

In another embodiment, the present invention provides a process for thepreparation of Canagliflozin pyrazole co-crystal, comprising providing asolution or suspension comprising canagliflozin and pyrazole in one ormore organic solvents and isolating the canagliflozin pyrazoleco-crystal.

The foregoing process for the preparation of canagliflozin pyrazoleco-crystal includes dissolving canagliflozin and pyrazole in one or moreorganic solvents as herein before defined, preferably in ethanol, at asuitable temperature, for example at about 30° C. to about refluxtemperature, preferably at about 50° C. to about reflux temperature.Then cooling the reaction mixture to less than 60° C. and thenoptionally an antisolvent such as n-heptane may be added toprecipitation of the resultant product. The precipitated Canagliflozinpyrazole co-crystals can be recovered by conventional techniques, forexample filtration.

In another embodiment, preparation of the co-crystals of the presentinvention significantly reduces the formation of unwanted alpha isomerthereby substantially pure beta isomer is resulted.

In another embodiment, the co-crystals of canagliflozin of the presentinvention may be used as an intermediate in obtaining high puritycanagliflozin.

In another embodiment, the present invention provides an improvedprocess for the preparation of canagliflozin from the co-crystals ofcanagliflozin.

In another embodiment, the present invention provides an improvedprocess for the preparation of canagliflozin from the CanagliflozinDL-pipecolic acid co-crystal as an intermediate.

In another embodiment, the present invention provides an improvedprocess for the preparation of canagliflozin; comprising:

-   -   a) preparing co-crystal of canagliflozin according to processes        described as above; and    -   b) converting the co-crystal of canagliflozin in to        canagliflozin; wherein the co-crystal former is selected from        the group comprising DL-pipecolic acid, D-pipecolic acid,        L-pipecolic acid, ammonia, nicotinic acid, isonicotinic acid,        pyridine, pyrazole, pyrazine-2-carboxylic acid, imidazole,        morpholine and the like.

The co-crystals of canagliflozin, for instance CanagliflozinDL-pipecolic acid co-crystal prepared by the process as described above,are dissolved in the one or more organic solvents. Examples of one ormore organic solvents used herein includes but are not limited toalcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol,iso-butanol and the like; ketones such as acetone, methyl isobutylketone, methyl ethyl ketone and the like; esters such as ethyl acetate,isopropyl acetate, isobutyl acetate and the like; ethers such astetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyltertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbonssuch as hexane, heptane, pentane and the like; aromatic hydrocarbonssuch as toluene, xylene and the like; halogenated hydrocarbons such asdichloromethane, chloroform and the like; nitriles such as acetonitrile,propionitrile, benzonitrile and the like or mixtures thereof. Preferablesolvent is ethyl acetate, isopropyl acetate, dichloromethane, toluene,methyl tertiary butyl ether and mixtures thereof.

The temperature suitable for dissolving the Canagliflozin DL-pipecolicacid co-crystal in the one or more solvents depends on the solvent usedand the amount of Canagliflozin DL-pipecolic acid co-crystal in thesolution. Typically, the temperature for dissolving CanagliflozinDL-pipecolic acid co-crystal in an organic solvent is at least about 25°C. to about reflux.

Then a suitable base may be added from about 0.5 to about 5 moleequivalents per mole of starting Canagliflozin DL-pipecolic acidco-crystal, preferably about 1 to about 4 moles.

Suitable base is either inorganic or organic base. The inorganic baseused herein is selected from the group comprising of alkali metalcarbonates such as sodium carbonate, potassium carbonate, cesiumcarbonate; alkali metal bicarbonates such as sodium bicarbonate,potassium bicarbonate and the like; alkali metal hydroxides such assodium hydroxide, potassium hydroxide and lithium hydroxide and thelike; alkali metal hydride such as sodium hydride, potassium hydride andthe like. The organic base used herein is selected from the groupcomprising of alkyl amines such as di-isopropyl ethylamine, triethylamine and the like; heterocyclic amines such as pyridine and the like.Preferably the base used herein is sodium bicarbonate, more preferablyan aqueous solution of sodium bicarbonate.

Isolation of canagliflozin may be carried out by known methods such asconcentrating the solvent from the solution by evaporation under spraydrying, agitated thin film dryer, under normal or atmospheric pressure;cooling the solution to precipitation and the like. Preferably isolationof canagliflozin can be carried out by separating the product containingorganic layer and concentrating it completely under vacuum to obtain aresidue. The canagliflozin product from the residue so obtained can berecovered using a suitable solvent.

The suitable solvent useful in the isolation of canagliflozin comprisesof aromatic hydrocarbons such as toluene, xylene and the like; aliphatichydrocarbons such as heptane, hexane, cyclohexane, cycloheptane, methylcyclohexane and the like; ethers such as methyl tertiary butyl ether,di-isopropyl ether, di-ethyl ether, tetrahydrofuran; ketones such asacetone, methyl ethyl ketone, methyl isobutyl ketone and the like.Preferably the suitable solvent used herein is cyclohexane and thecrystallization can be carried out by mixing the residue obtained fromthe above in cyclohexane at a temperature of about 25° C. to refluxtemperature, preferably at about 25° C. to about 35° C. The resultantcanagliflozin can be isolated by conventional techniques known in theart, for example filtration.

The resultant canagliflozin may optionally be further dried. Drying canbe suitably carried out in a tray dryer, vacuum oven, air oven,fluidized bed drier, spin flash dryer, flash dryer and the like. Thedrying can be carried out at a temperature ranging from about 30° C. toabout 80° C. for a time period ranging from about 1 hour to about 12hours.

In another embodiment, canagliflozin obtained according to the presentinvention is in substantially pure form.

In another embodiment, canagliflozin obtained according to the presentinvention is in substantially amorphous form.

In another embodiment, the present invention provides Canagliflozinhaving a chemical purity greater than or equal to about 97%, as measuredby HPLC, preferably about 98% as measured by HPLC, and more preferablyabout 99.5%, as measured by HPLC and substantially free of alpha isomerimpurity.

As used herein, the term “substantially free” refers to Canagliflozinhaving less than 2% as measured by HPLC of alpha isomer impurity;preferably less than 1% of alpha isomer impurity as measured by HPLC,more preferably less than about 0.5% of alpha isomer impurity asmeasured by HPLC.

In another embodiment, the present invention provides co-crystals ofdapagliflozin.

In another embodiment, the present invention provides co-crystals ofdapagliflozin, wherein the co-crystal former is selected from the groupcomprising DL-pipecolic acid, D-pipecolic acid, L-pipecolic acid,ammonia, nicotinic acid, isonicotinic acid, pyridine, pyrazole,pyrazine-2-carboxylic acid, imidazole, morpholine and the like.

In another embodiment, the present invention provides a process for thepreparation of co-crystals of dapagliflozin, comprising:

-   -   a) providing a solution or suspension comprising dapagliflozin        and a co-crystal former in one or more solvents; and    -   b) isolating the co-crystals of dapagliflozin; wherein the        co-crystals former is selected from the group comprising        DL-pipecolic acid, D-pipecolic acid, L-pipecolic acid, ammonia,        nicotinic acid, isonicotinic acid, pyridine, pyrazole,        pyrazine-2-carboxylic acid, imidazole, morpholine and the like.

The step of providing a solution or suspension includes any form ofdapagliflozin that may be mixed with one or more solvents andco-crystals former or includes any form of dapagliflozin that may becombined with one or more solvents and then the co-crystals former maybe mixed with the resulting solution or slurry. Alternatively, themixture may be formed by adding dapagliflozin and co-crystals former atthe same time in to one or more organic solvents.

Examples of one or more solvents of step a) includes but are not limitedto esters such as methyl acetate, ethyl acetate, isopropyl acetate,n-propyl acetate, n-butyl acetate, t-butyl acetate and the like;alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol,isobutanol and the like; ethers such as tetrahydrofuran, dimethyl ether,diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and thelike, ketones such as acetone, methyl ethyl ketone, methyl isobutylketone and the like, cyclic hydrocarbon solvents such as hexane,heptane, cyclohexane and the like, halogenated hydrocarbon solvents suchas dichloromethane, dichloroethane, chloroform and the like, nitrilessuch as acetonitrile, propionitrile and the like; water or mixturesthereof; preferably isopropyl acetate, ethanol, isopropanol; water ormixture thereof.

The temperature suitable for dissolving or suspending the dapagliflozinin one or more organic solvents depends on the solvent used and theamount of dapagliflozin in the reaction mass. Typically, the solution orsuspension is heated at a temperature of at least about 30° C. to aboutreflux.

The step b) of the foregoing process, the isolation of co-crystals ofdapagliflozin may be carried out by concentration, by subjecting thesolution to heating, cooling the solution to precipitation,crystallization, solvent precipitation, spray drying, freeze drying,agitated thin film evaporator (ATFE), evaporation on rotary evaporatorunder vacuum and the like. Preferably the reaction solution may becooled to precipitation followed by stirring the reaction mixture forsufficient period of time. Optionally, an anti-solvent may be added toimprove the product precipitation prior to cooling the reaction mass.The co-crystals of dapagliflozin can be recovered by any conventionaltechnique known in the art, for example, filtration. The resultantco-crystals of dapagliflozin may optionally be further purified.

In another embodiment, the present invention provides co-crystals ofdapagliflozin having a chemical purity greater than or equal to about97%, as measured by HPLC, preferably about 98% as measured by HPLC, andmore preferably about 99.5%, as measured by HPLC.

In another embodiment, some of the co-crystals of the present inventionmay exist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the co-crystals of the presentinvention may form solvates with water (i.e., hydrates) or commonorganic solvents, and such solvates are also intended to be encompassedwithin the scope of this invention.

In another embodiment, the co-crystals of dapagliflozin recovered usingthe process of the present invention described above includes one ormore co-crystals of dapagliflozin such as dapagliflozin DL-pipecolicacid co-crystals, dapagliflozin D-pipecolic acid co-crystals anddapagliflozin L-pipecolic acid co-crystals.

In another embodiment, the present invention provides co-crystals ofdapagliflozin, wherein the co-crystal is selected from DL-pipecolicacid, D-pipecolic acid or L-pipecolic acid.

In another embodiment, the present invention provides dapagliflozinDL-pipecolic acid co-crystals.

In another embodiment, the present invention provides a process for thepreparation of dapagliflozin DL-pipecolic acid co-crystals, comprising:

-   -   a) providing a solution or suspension comprising dapagliflozin        and DL-pipecolic acid in one or more solvents; and    -   b) isolating the dapagliflozin DL-pipecolic acid co-crystals.

The step of providing a solution or suspension comprising dapagliflozinand DL-pipecolic acid in one or more solvent may include heating todissolve. The temperature suitable for dissolving or suspending thedapagliflozin in the one or more solvents depends on the solvent usedand the amount of dapagliflozin in the reaction mass. Typically, thesolution or suspension is heated at a temperature of at least about 30°C. to about reflux. Examples of one or more c solvents used in step a)are same as solvents defined just as above.

The step b) of the foregoing process, isolation of the dapagliflozinDL-pipecolic acid co-crystals obtained may be carried out by optionallyallowing the reaction mass to gradually cool to a temperature of lessthan 30° C. and the resultant dapagliflozin DL-pipecolic acidco-crystals can be isolated by conventional techniques, for example byfiltration. The resultant wet product may optionally be further dried.Drying can be suitably carried out in a tray dryer, vacuum oven, airoven, fluidized bed drier, spin flash dryer, flash dryer and the like.

In another embodiment, dapagliflozin DL-pipecolic acid co-crystalsrecovered using the process as described just above is substantially acrystalline form.

In another embodiment, the present invention provides dapagliflozinDL-pipecolic acid co-crystals characterized by X-Ray powder diffraction(XRD) pattern substantially in accordance with FIG. 09.

In another embodiment, the present invention provides dapagliflozinDL-pipecolic acid co-crystals characterized by an X-Ray powderdiffraction (XRD) pattern having one or more peaks at about 3.91, 7.83,8.41, 9.38, 11.76, 15.38, 15.65, 16.26, 16.99, 17.62, 17.95, 18.36,19.96, 20.28, 21.29, 21.97, 23.02, 23.65, 24.68, 26.72, 30.43 and31.34±0.2° 2θ.

In another embodiment, the present invention provides dapagliflozinDL-pipecolic acid co-crystals characterized by a ¹H NMR Spectrumsubstantially in accordance with FIG. 10.

In another embodiment, the present invention provides dapagliflozinDL-pipecolic acid co-crystals characterized by a differential scanningcalorimetry (DSC) thermogram substantially in accordance with FIG. 11.

In another embodiment, the present invention provides dapagliflozinDL-pipecolic acid co-crystals characterized by a thermogravimetricanalysis (TGA) curve substantially in accordance with FIG. 12.

In another embodiment, the present invention provides dapagliflozinDL-pipecolic acid co-crystals characterized by X-Ray powder diffraction(XRD) pattern substantially in accordance with FIG. 09, a ¹H NMRSpectrum substantially in accordance with FIG. 10, a differentialscanning calorimetry (DSC) thermogram substantially in accordance withFIG. 11 and a thermogravimetric analysis (TGA) curve substantially inaccordance with FIG. 12.

In another embodiment, the present invention provides dapagliflozinD-pipecolic acid co-crystals.

In another embodiment, the present invention provides a process for thepreparation of dapagliflozin D-pipecolic acid co-crystals, comprising:

-   -   a) providing a solution or suspension comprising dapagliflozin        and D-pipecolic acid in one or more solvents; and    -   b) isolating the dapagliflozin D-pipecolic acid co-crystals.

The step of providing a solution or suspension comprising dapagliflozinand D-pipecolic acid in one or more solvent may include heating todissolve. The temperature suitable for dissolving or suspending thedapagliflozin in the one or more solvents depends on the solvent usedand the amount of dapagliflozin in the reaction mass. Typically, thesolution or suspension is heated at a temperature of at least about 30°C. to about reflux. Examples of one or more organic solvents used instep a) are same as solvents defined just as above.

The step b) of the foregoing process, isolation of the dapagliflozinD-pipecolic acid co-crystals obtained may be carried out by optionallyallowing the reaction mass to gradually cool to a temperature of lessthan 30° C. and the resultant dapagliflozin D-pipecolic acid co-crystalscan be isolated by conventional techniques, for example by filtration.The resultant wet product may optionally be further dried. Drying can besuitably carried out in a tray dryer, vacuum oven, air oven, fluidizedbed drier, spin flash dryer, flash dryer and the like.

In another embodiment, dapagliflozin D-pipecolic acid co-crystalsrecovered using the process as described just above is substantially acrystalline form.

In another embodiment, the present invention provides dapagliflozinD-pipecolic acid co-crystals characterized by X-Ray powder diffraction(XRD) pattern substantially in accordance with FIG. 13.

In another embodiment, the present invention provides dapagliflozinL-pipecolic acid co-crystals.

In another embodiment, the present invention provides a process for thepreparation of dapagliflozin L-pipecolic acid co-crystals, comprising:

-   -   a) providing a solution or suspension comprising dapagliflozin        and L-pipecolic acid in one or more solvents; and    -   b) isolating the dapagliflozin L-pipecolic acid co-crystals.

The step of providing a solution or suspension comprising dapagliflozinand L-pipecolic acid in one or more solvent may include heating todissolve. The temperature suitable for dissolving or suspending thedapagliflozin in the one or more solvents depends on the solvent usedand the amount of dapagliflozin in the reaction mass. Typically, thesolution or suspension is heated at a temperature of at least about 30°C. to about reflux. Examples of one or more organic solvents used instep a) are same as organic solvents defined just as above.

The step b) of the foregoing process, isolation of the dapagliflozinL-pipecolic acid co-crystals obtained may be carried out by optionallyallowing the reaction mass to gradually cool to a temperature of lessthan 30° C. and the resultant dapagliflozin L-pipecolic acid co-crystalscan be isolated by conventional techniques, for example by filtration.The resultant wet product may optionally be further dried. Drying can besuitably carried out in a tray dryer, vacuum oven, air oven, fluidizedbed drier, spin flash dryer, flash dryer and the like.

In another embodiment, dapagliflozin L-pipecolic acid co-crystalsrecovered using the process as described just above is substantially acrystalline form.

In another embodiment, the present invention provides dapagliflozinL-pipecolic acid co-crystals characterized by X-Ray powder diffraction(XRD) pattern substantially in accordance with FIG. 14.

In another embodiment, the present invention provides solvates ofdapagliflozin.

In another embodiment, the present invention provides dapagliflozin2,3-butanediol solvate.

In another embodiment, the present invention provides crystallinedapagliflozin 2,3-butanediol solvate.

In another embodiment, crystalline dapagliflozin 2,3-butanediol solvatecharacterized by X-Ray powder diffraction (XRD) pattern substantially inaccordance with FIG. 15.

In another embodiment, the present invention provides crystallinedapagliflozin 2,3-butanediol solvate characterized by X-Ray powderdiffraction (XRD) pattern having one or more peaks at about 3.69, 8.62,9.52, 10.70, 14.63, 15.74, 16.09, 16.60, 18.33, 18.55, 19.82, 20.15,20.56, 21.20, 21.79, 22.75, 23.39, 24.23, 24.68, 25.15, 25.76, 26.50,27.03, 27.36, 29.48, 29.94, 30.60, 31.66, 32.56, 34.21 and 36.95±0.2°2θ.

In another embodiment, the present invention provides crystallinedapagliflozin 2,3-butanediol solvate characterized by a ¹H NMR Spectrumsubstantially in accordance with FIG. 16.

In another embodiment, the present invention provides crystallinedapagliflozin 2,3-butanediol solvate characterized by a differentialscanning calorimetry (DSC) thermogram substantially in accordance withFIG. 17.

In another embodiment, the present invention provides crystallinedapagliflozin 2,3-butanediol solvate characterized by athermogravimetric analysis (TGA) curve substantially in accordance withFIG. 18.

In another embodiment, the present invention provides a process for thepreparation of dapagliflozin 2,3-butanediol solvate, comprising:

-   -   a) dissolving dapagliflozin or a solvate or a co-crystal in an        organic solvent at a temperature of about 25° C. to reflux,    -   b) treating the above solution with 2,3-butanediol,    -   c) optionally adding seed crystals of dapagliflozin        2,3-butanediol solvate,    -   d) adding an anti-solvent to the reaction mass, and    -   e) isolating dapagliflozin 2,3-butanediol solvate.

Step a) of the forgoing process involves the dissolution ofdapagliflozin in an organic solvent, wherein the organic solventincludes but are not limited to ethers such as methyl tertiary butylether, tetrahydrofuran, dimethyl ether, diisopropyl ether, 1,4-dioxaneand the like; esters such as methyl acetate, ethyl acetate, isopropylacetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and thelike; alcohols such as methanol, ethanol, isopropanol, n-propanol,n-butanol, isobutanol and the like; ketones such as acetone, methylethyl ketone, methyl isobutyl ketone and the like; nitriles such asacetonitrile, propionitrile or mixtures thereof. Preferably the organicsolvent includes methyl tertiary butyl ether, ethyl acetate, isopropylacetate and mixtures thereof. Optionally the reaction mixture may beheated to complete dissolution of the contents in the solvent. Thesuitable temperature may be selected from room temperature to aboutreflux temperature of the solvent used, preferably at about 20° C. toabout 75° C. Then the step a) solution of dapagliflozin is treated with2,3-butanediol and the obtained solution is further stirred.

Adding the solution obtained in step b) to the anti-solvent, or addingan anti-solvent to the solution obtained in step b) to effect thecrystallization of the product.

The anti-solvent used for step d) includes but are not limited to water,hydrocarbon solvents such as n-pentane, n-hexane, n-heptane,cyclohexane, methyl cyclohexane, cycloheptane or mixture thereof;preferably heptane, cyclohexane or cycloheptane.

Optionally seed crystals of dapagliflozin 2,3-butanediol solvate may beadded either prior to addition of anti-solvent to the reaction solutionor during the addition of anti-solvent. The seed crystals can beprepared according the process of the present invention.

In step e) of the foregoing process, the isolation of crystallinedapagliflozin 2,3-butanediol solvate may be carried out bycrystallization, solvent precipitation, concentration by subjecting thesolution to heating, spray drying, freeze drying, evaporation on rotaryevaporator under vacuum, agitated thin film evaporator (ATFE) and thelike. Preferably the reaction solution may be cooled to precipitationfollowed by stirring the reaction mixture for sufficient period of timeand the resultant dapagliflozin 2,3-butanediol solvate can be recoveredby conventional techniques, for example filtration. The product thusisolated may be optionally dried.

In another embodiment, the present invention provides a process for thepreparation of amorphous form of dapagliflozin, wherein the processinvolves one or more solid forms of dapagliflozin of the invention asintermediates.

In another embodiment, the co-crystals of dapagliflozin of the presentinvention may be used as an intermediate in the process of obtaininghigh purity dapagliflozin.

In another embodiment, the present invention provides the use of one ormore co-crystals of dapagliflozin, preferably DL-pipecolic acidco-crystals, D-pipecolic acid co-crystals or L-pipecolic acidco-crystals in the preparation of high purity amorphous dapagliflozin.

In another embodiment, the dapagliflozin 2,3-butanediol solvate of thepresent invention may be used as an intermediate in the process ofobtaining high purity dapagliflozin.

In another embodiment, the present invention provides a process for thepreparation of amorphous dapagliflozin, comprising:

-   -   a) dissolving or suspending dapagliflozin co-crystals in a        suitable solvent;    -   b) optionally treating the step a) reaction mass with a suitable        base or an acid;    -   c) extracting dapagliflozin into an organic solvent; and    -   d) removing the solvent to obtain amorphous form of        dapagliflozin.

The dapagliflozin co-crystals used in step a) includes but are notlimited to amino acid co-crystals such as proline, alanine, valine,leucine, isoleucine, phenyl alanine, tryptophan, glycine, serine,threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine,histidine, aspartic acid, glutamic acid, pipecolic acid, wherein theamino acid used may be either optically active or racemic form; ammonia,nicotinic acid, isonicotinic acid, pyridine, pyrazole,pyrazine-2-carboxylic acid, imidazole, morpholine, lactose and citricacid.

Preferably the dapagliflozin co-crystals used herein are selected fromdapagliflozin DL-pipecolic acid, D-pipecolic acid or L-pipecolic acids,which are prepared by the processes as described above.

The solvent used herein for dissolution of dapagliflozin co-crystals isselected from water or mixture of water and an organic solvent; whereinorganic solvent is selected from alcohols such as methanol, ethanol,1-propanol, isopropanol, butanol, isobutanol, t-butanol or mixturesthereof; esters such as methyl acetate, ethyl acetate, isopropyl acetateand the like; preferably water, or a mixture of water and an organicsolvent such as ethyl acetate.

The temperature suitable for dissolving or suspending the dapagliflozinco-crystals in the one or more suitable solvents depends on the solventused and the amount of dapagliflozin co-crystals in the reaction mass.Typically, the solution or suspension is stirred at a temperature of atleast about 20° C. to about reflux.

Step b) of the foregoing process involves treating the step a) reactionmass with a base or an acid before extracting the dapagliflozin into anorganic solvent. The base or acid may be added from about 0.5 to about 5mole equivalents per mole of starting co-crystals of dapagliflozin,preferably about 1 to about 4 moles.

Suitable base is either inorganic or organic base. The inorganic base isselected from the group comprising alkali metal carbonates such assodium carbonate, potassium carbonate, cesium carbonate; alkali metalbicarbonates such as sodium bicarbonate, potassium bicarbonate and thelike; alkali metal hydroxides such as sodium hydroxide, potassiumhydroxide and lithium hydroxide and the like. The organic base usedherein is selected from the group comprising of alkyl amines such asdi-isopropyl ethylamine, triethyl amine and the like; heterocyclicamines such as pyridine and the like. The suitable base can be addedeither as a solution in one or more solvents as herein before defined orit may be added directly to the solution of co-crystals of dapagliflozinin one or more solvents.

Suitable acid is selected from the group comprising of hydrochloricacid, sulfuric acid, acetic acid or mixtures thereof.

Examples of organic solvents used for extraction herein includes but arenot limited to esters such as methyl acetate, ethyl acetate, isopropylacetate n-propyl acetate, n-butyl acetate, t-butyl acetate and the like;ethers such as dimethyl ether, diisopropyl ether, methyl tertiary butylether, 1,4-dioxane and the like; aliphatic hydrocarbons such as hexane,heptane, pentane and the like; aromatic hydrocarbons such as toluene,xylene and the like; halogenated hydrocarbons such as dichloromethane,chloroform and the like or mixtures thereof.

Isolation of dapagliflozin can be carried out by separating the productcontaining organic layer and removal of solvent. Techniques which may beused for the removal of solvent include distillation, distillation undervacuum, spray drying, agitated thin film drying (“ATFD”) and freezedrying (lyophilization). Preferably isolation of dapagliflozin can becarried out by removal of solvent by distillation under vacuum.

In another embodiment, the present invention provides a process for thepreparation of amorphous dapagliflozin, comprising:

-   -   a) dissolving or suspending dapagliflozin co-crystals in a        suitable solvent,    -   b) treating the step a) reaction mass with a suitable base or an        acid,    -   c) optionally extracting dapagliflozin into an organic solvent,    -   d) removing the solvent to obtain a residue,    -   e) dissolving the residue in an organic solvent to obtain a        solution,    -   f) adding an anti-solvent to the step e) solution or vice-versa,    -   g) optionally seeding with amorphous dapagliflozin, and    -   h) isolating amorphous dapagliflozin.

The co-crystals of dapagliflozin of step a) comprises one or more ofco-crystals as defined herein above and the suitable solvent of step a)also comprises one or more of solvents as defined herein above.

Step b) of the foregoing process involves the treatment of step a)reaction mass with a suitable base or an acid before extracting thedapagliflozin into an organic solvent, wherein suitable base or an acidof step b) and extraction solvent of step c) are defined herein above.

Step d) of the foregoing process involves the removal of solvent toobtain dapagliflozin residue, wherein removal of solvent includesevaporation, distillation or distillation under vacuum; preferablydistillation under vacuum.

The residue obtained is dissolved in an organic solvent, wherein theorganic solvent includes but are not limited to ethers such as methyltertiary butyl ether, tetrahydrofuran, dimethyl ether, diisopropylether, 1,4-dioxane and the like; esters such as methyl acetate, ethylacetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t-butylacetate and the like; alcohols such as methanol, ethanol, isopropanol,n-propanol, n-butanol, isobutanol and the like; ketones such as acetone,methyl ethyl ketone, methyl isobutyl ketone and the like or mixturesthereof.

The dissolution temperatures may range from about 20° C. to about refluxtemperature of the solvent. Then, the amorphous form can be precipitatedby mixing an anti-solvent with the reaction solution. The anti-solventmay be either added to step e) solution or step e) solution is added toanti solvent.

The anti-solvent used herein includes but are not limited to water,hydrocarbon solvents such as n-pentane, n-hexane, 3-methylpentane,2,3-dimethylbutane, n-heptane, 2,3-dimethylpentane, 2,4-dimethylpentane,3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane,3-methylheptane, cyclohexane, methylcyclohexane, cycloheptane ormixtures thereof; preferably water, heptane or cycloheptane.

The anti-solvent may be added by a single lot manner or by a multiplelots. Prior to addition of anti-solvent, reaction mass temperature maybe cooled to less than 30° C., preferably less than 20°. During each lotof anti-solvent addition, reaction mass may be maintained for a minimumof about 5 minutes for better precipitation of the product.

Optionally, amorphous dapagliflozin seed may be added either prior toaddition of anti-solvent to the reaction solution or during the additionof anti-solvent. The amorphous dapagliflozin seed can be preparedaccording the process of the present invention or can be prepared by anyknown methods.

The step of isolation of the resultant amorphous form can be carried outby conventional technique known in the art, for example filtration. Theresultant wet product may optionally be further dried. Drying can besuitably carried out in a tray dryer, vacuum oven, air oven, fluidizedbed drier, spin flash dryer, flash dryer and the like.

In another embodiment, the present invention provides a process for thepreparation of amorphous dapagliflozin, comprising:

-   -   a) providing a solution of dapagliflozin in a solvent selected        from the group consisting of esters, ethers, alcohols, ketones,        nitriles or mixtures thereof, and    -   b) removing the solvent from the solution to obtain amorphous        form of Dapagliflozin.

Step a) of the forgoing process involves the dissolution ofdapagliflozin in a solvent, wherein the solvent includes but are notlimited to esters such as methyl acetate, ethyl acetate, isopropylacetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and thelike; ethers such as methyl tertiary butyl ether, tetrahydrofuran,dimethyl ether, diisopropyl ether, 1,4-dioxane and the like; alcoholssuch as methanol, ethanol, isopropanol, n-propanol, n-butanol,isobutanol and the like; ketones such as acetone, methyl ethyl ketone,methyl isobutyl ketone and the like; nitriles such as acetonitrile,propionitrile or mixtures thereof; preferably methyl acetate, isopropylacetate, ethyl acetate, methyl tertiary butyl ether or mixtures thereof.

The dissolution temperatures may range from about 30° C. to about refluxtemperature of the solvent. The step of removal of solvent may becarried out by one or more techniques of distillation, distillationunder vacuum, spray drying, agitated thin film drying (“ATFD”), andfreeze drying (lyophilization). The resultant wet product may optionallybe further dried. Drying can be suitably carried out in a tray dryer,vacuum oven, air oven, fluidized bed drier, spin flash dryer, flashdryer and the like.

In another embodiment, the present invention provides a process for thepreparation of amorphous dapagliflozin, comprising:

-   -   a) providing a solution of dapagliflozin in a solvent selected        from the group consisting of esters, ethers, alcohols, ketones,        nitriles or mixtures thereof,    -   b) adding an anti-solvent to the solution or vice versa,    -   c) optionally seeding with amorphous dapagliflozin, and    -   d) isolating amorphous form of dapagliflozin; wherein the        anti-solvent is selected from the group consisting of water,        hydrocarbons solvents, ether solvents or mixtures thereof.

Step a) of the foregoing process involves providing a solution ofdapagliflozin in a solvent or mixture of solvent. The solution for stepa) can be obtained by the known methods that include: (i) direct use ofa reaction mixture containing dapagliflozin that is obtained in thecourse of its synthesis; or (ii) dissolving dapagliflozin in one or moreof organic solvent.

The organic solvent comprises one or more of solvents selected fromesters such as methyl acetate, ethyl acetate, isopropyl acetate,n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; etherssuch as methyl tertiary butyl ether, tetrahydrofuran, dimethyl ether,diisopropyl ether, 1,4-dioxane and the like; alcohols such as methanol,ethanol, isopropanol, n-propanol, n-butanol, isobutanol and the like;ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone andthe like; nitriles such as acetonitrile, propionitrile or mixturesthereof;

preferably methyl acetate, isopropyl acetate, ethyl acetate, methyltertiary butyl ether or mixtures thereof.

The dissolution temperatures may range from about 20° C. to about refluxtemperature of the solvent. Then, the amorphous form can be precipitatedby mixing an anti-solvent with the reaction solution. The anti-solventmay be either added to step a) solution or step a) solution is added toanti solvent.

The anti-solvent used herein includes but are not limited to water,hydrocarbons solvents such as n-pentane, n-hexane, 3-methylpentane,2,3-dimethylbutane, n-heptane, 2,3-dimethylpentane, 2,4-dimethylpentane,3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane,3-methylheptane, cyclohexane, methylcyclohexane, cycloheptane ormixtures thereof; preferably water, heptane or cycloheptane.

The anti-solvent may be added by a single lot manner or by a multiplelots. Prior to addition of anti-solvent, reaction mass temperature maybe cooled to less than 30° C., preferably less than 20°. During each lotof anti-solvent addition, reaction mass may be maintained for a minimumof about 5 minutes to better precipitation of the product.

Optionally, amorphous dapagliflozin seed may be added either prior toaddition of anti-solvent to the reaction solution or during the additionof anti-solvent. The amorphous dapagliflozin seed can be preparedaccording the process of the present invention or can be prepared by anyknown methods.

The step of isolation of the resultant amorphous form can be carried outby conventional technique known in the art, for example filtration. Theresultant wet product may optionally be further dried. Drying can besuitably carried out in a tray dryer, vacuum oven, air oven, fluidizedbed drier, spin flash dryer, flash dryer and the like.

In another embodiment, the present invention provides co-crystals ofempagliflozin.

In accordance with another embodiment, the present invention providesco-crystals of empagliflozin, wherein the co-crystal former is selectedfrom the group comprising DL-pipecolic acid, D-pipecolic acid,L-pipecolic acid, ammonia, nicotinic acid, isonicotinic acid, pyridine,pyrazole, pyrazine-2-carboxylic acid, imidazole, morpholine, proline andthe like.

In accordance with another embodiment, the present invention provides aprocess for the preparation of co-crystals of empagliflozin, comprising:

-   -   a) providing a solution or suspension comprising empagliflozin        and a co-crystal former, and    -   b) isolating the co-crystals of empagliflozin; wherein the        co-crystal former is selected from the group comprising        DL-pipecolic acid, D-pipecolic acid, L-pipecolic acid, ammonia,        nicotinic acid, isonicotinic acid, pyridine, pyrazole,        pyrazine-2-carboxylic acid, imidazole, morpholine, proline and        the like.

The step of providing a solution or suspension includes any form ofempagliflozin that may be mixed with one or more solvents and co-crystalformer or includes any form of empagliflozin that may be combined withone or more solvents and then the co-crystal former may be mixed withthe resulting solution or slurry. Alternatively, the mixture may beformed by adding empagliflozin and co-crystal former at the same time into one or more solvents.

Examples of one or more solvents of step a) includes but are not limitedto esters such as methyl acetate, ethyl acetate, isopropyl acetate,n-propyl acetate, n-butyl acetate, t-butyl acetate and the like;alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol,isobutanol and the like; ethers such as tetrahydrofuran, dimethyl ether,diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and thelike; ketones such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; aliphatic hydrocarbon solvents such as hexane,heptane, cyclohexane and the like; halogenated hydrocarbon solvents suchas dichloromethane, dichloroethane, chloroform and the like; nitrilessuch as acetonitrile, propionitrile and the like; water or mixturesthereof; preferably the solvent of step a) is n-butanol, ethanol oracetone; more preferably n-butanol.

The temperature suitable for dissolving or suspending the empagliflozinin one or more solvents depends on the solvent used and the amount ofempagliflozin in the reaction mass. Typically, the solution orsuspension is heated at a temperature of at least about 30° C. to aboutreflux.

The step b) of the foregoing process, the isolation of co-crystals ofempagliflozin may be carried out by concentration by subjecting thesolution to heating, cooling the solution to precipitation,crystallization, solvent precipitation, spray drying, freeze drying,agitated thin film evaporator (ATFE), evaporation on rotary evaporatorunder vacuum and the like. Preferably the reaction solution may becooled to precipitation followed by stirring the reaction mixture forsufficient period of time. Optionally, an anti-solvent can be added toimprove the product precipitation prior to cooling the reaction mass.The anti-solvent used herein for example water. The co-crystals ofempagliflozin can be recovered by any conventional technique known inthe art, for example, filtration. The resultant co-crystals ofempagliflozin may optionally be further purified.

In another embodiment, the present invention provides co-crystals ofempagliflozin having a chemical purity greater than or equal to about97%, as measured by HPLC, preferably about 98% as measured by HPLC, andmore preferably about 99.5%, as measured by HPLC.

In another embodiment, some of the co-crystals of the present inventionmay exist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the co-crystals of the presentinvention may form solvates with water (i.e., hydrates) or commonorganic solvents, and such solvates are also intended to be encompassedwithin the scope of this invention.

In another embodiment, the co-crystals of empagliflozin recovered usingthe process of the present invention described above includesempagliflozin DL-pipecolic acid co-crystals.

In another embodiment, the present invention provides empagliflozinDL-pipecolic acid co-crystal.

In another embodiment, the present invention provides empagliflozinDL-pipecolic acid co-crystal hydrate.

In another embodiment, the present invention provides a process for thepreparation of empagliflozin DL-pipecolic acid co-crystals, comprising:

-   -   a) providing a solution or suspension comprising empagliflozin        and DL-pipecolic acid in one or more solvents; and    -   b) isolating the empagliflozin DL-pipecolic acid co-crystals.

The step of providing a solution or suspension comprising empagliflozinand DL-pipecolic acid in one or more solvent may include heating todissolve. The temperature suitable for dissolving or suspending theempagliflozin in the one or more solvents depends on the solvent usedand the amount of empagliflozin in the reaction mass. Typically, thesolution or suspension is heated at a temperature of at least about 30°C. to about reflux. Examples of one or more solvents used in step a) aresame as solvents defined just as above.

The step b) of the foregoing process, isolation of the empagliflozinDL-pipecolic acid co-crystal obtained may be carried out by optionallyallowing the reaction mass to gradually cool to a temperature of lessthan 30° C. and the resultant empagliflozin DL-pipecolic acidco-crystals can be isolated by conventional techniques, for example byfiltration. The resultant wet product may optionally be further dried.Drying can be suitably carried out in a tray dryer, vacuum oven, airoven, fluidized bed drier, spin flash dryer, flash dryer and the like.

In another embodiment, empagliflozin DL-pipecolic acid co-crystals arerecovered using the process as described just above is a hydrate form.

In another embodiment, empagliflozin DL-pipecolic acid monohydrateco-crystals is recovered using the process as described just above issubstantially a crystalline form.

In another embodiment, the present invention provides empagliflozinDL-pipecolic acid co-crystals characterized by X-Ray powder diffraction(XRD) pattern substantially in accordance with FIG. 21.

In another embodiment, the present invention provides empagliflozinDL-pipecolic acid co-crystals characterized by X-Ray powder diffraction(XRD) pattern having one or more peaks at about 5.5, 9.8, 11.0, 12.0,12.2, 14.7, 15.8, 16.3, 17.3, 17.7, 18.1, 18.5, 18.9, 19.6, 20.7, 21.1,22, 22.5, 23.5, 24.5, 25.0, 26.4, 27.2, 28.1, 29, 29.8, 30.9, 31.4,33.7, 35.3, 36.7, 39.6±0.2° 2θ.

In another embodiment, the present invention provides empagliflozinDL-pipecolic acid co-crystals characterized by a ¹H NMR Spectrumsubstantially in accordance with FIG. 22.

In another embodiment, the present invention empagliflozin DL-pipecolicacid co-crystals characterized by a differential scanning calorimetry(DSC) thermogram substantially in accordance with FIG. 23.

In another embodiment, the present invention provides empagliflozinDL-pipecolic acid co-crystals characterized by a thermogravimetricanalysis (TGA) curve substantially in accordance with FIG. 24.

In another embodiment, the present invention provides empagliflozinDL-pipecolic acid co-crystals characterized by X-Ray powder diffraction(XRD) pattern substantially in accordance with FIG. 21, a ¹H NMRSpectrum substantially in accordance with FIG. 22; a differentialscanning calorimetry (DSC) thermogram substantially in accordance withFIG. 23 and a thermogravimetric analysis (TGA) curve substantially inaccordance with FIG. 24.

The solid forms of SGLT2 inhibitors as described above may have greaterstability, bioavailability, and having desired pharmacological,pharmacokinetic and pharmacodynamic effects as compared to the SGLT2inhibitor individually.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising at least one of the solid forms of SGLT2inhibitors described above and at least one or more pharmaceuticallyacceptable excipients.

The present invention is further directed to methods for the treatmentand or prevention of glucose related disorders. As used herein, the term“glucose related disorder” shall be defined as any disorder, which ischaracterized by or is developed as a consequence of elevated glucoselevels. Glucose-related disorders shall include diabetes mellitus,diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayedwound healing, insulin resistance, hyperglycemia, hyperinsulinemia,elevated blood levels of fatty acids, elevated blood levels of glucose,hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabeticcomplications, atherosclerosis, or hypertension. In particular, the“glucose related-disorder” is diabetes mellitus (type 1 and type 2diabetes mellitus, etc.), diabetic complications (such as diabeticretinopathy, diabetic neuropathy, diabetic nephropathy), obesity, orpostprandial hyperglycemia.

Solid forms of SGLT2 inhibitors were characterized by one or more of thetechniques such as PXRD, TGA, DSC and IR techniques.

The X-Ray powder diffraction can be measured by X-ray powderdiffractometer equipped with a Cu-anode ([λ]=1.54 Angstrom), X-raysource operated at 30 kV, 15 mA. Two-theta calibration is performedusing an NIST SRM 640c Si standard. The sample was analyzed using thefollowing instrument parameters: measuring range=3-45° 2θ; stepwidth=0.020°; and scan speed=5° 2θ/minute; or

by using PANalytical X'per³pro X-ray powder Diffractometer equipped witha Cu-anode ([λ]=1.54 Angstrom), X-ray source operated at 45 kV, 40 mA.Two-theta calibration is performed using an NIST SRM 640c Si standard.The sample was analyzed using the following instrument parameters:measuring range=3-45° 20; step size=0.01°; and Time per step=43 sec.

All TGA data reported herein were analyzed using TGA Q500 V 20.13 build39 in platinum pan with a temperature rise of about 10° C./min in therange of about 30° C. to about 250° C.

All DSC data reported herein were analyzed in hermitically sealedaluminium pan, with a blank hermitically sealed aluminium pan as thereference and were obtained using DSC (DSC Q200, TA instrumentation,Waters) at a scan rate of 10° C. per minute with an Indium standard.

Or

in hermitically sealed pinhole aluminium pan, with a blank hermiticallysealed aluminium pan as the reference and were obtained using DSC (DSCQ200, TA instrumentation, Waters) at a scan rate of 10° C. per minutewith an Indium standard.

As used herein, unless otherwise noted, the term “substantially pureform” shall mean that the percent of impurities in the isolated solidforms is less than about 5% by weight as measured by HPLC, preferablyless than about 2%, more preferably less than about 1%, most preferablyless than about 0.5%.

EXAMPLES

The present invention is further illustrated by the following examples,which are provided by way of illustration only and should not beconstrued to limit the scope of the invention.

Example 1: Preparation of Canagliflozin

In a round bottom flask equipped with reflux condenser,1-(1-methoxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]-benzene(10 gms) was dissolved in mixture of methylene chloride (100 ml) andacetonitrile (20 ml) at 25-30° C. under nitrogen atmosphere. Triethylsilane (7.35 gms) was added and the reaction mass was stirred for 10 minat 25-30° C. The reaction mass was cooled to −45 to −40° C., added dropwise boron trifluoride ethyl ether complex (8 ml) and the mixture wasstirred for 1.0 hr at same temperature. Further, the reaction mass wasstirred at 0-5° C. for 2 hrs and quenched by adding saturated sodiumbicarbonate solution (100 ml). The resulting organic layer wasseparated, washed with water (50 ml) and the organic solvent wasdistilled out under vacuum to obtain Canagliflozin (8.5 gms).

HPLC purity: 88.249%,

Alpha isomer content by HPLC: 2.76%.

Example 2: Preparation of Canagliflozin DL-Pipecolic Acid Co-Crystal:(Ethanol+Heptane)

To a round bottom flask equipped with reflux condenser, ethanol (100 ml)was added followed by Canagliflozin (5 gms; alpha isomer content byHPLC: 2.76%). The contents were heated to 55-60° C. and DL-Pipecolicacid (1.74 gms; source: Alfa aesar) was added at 55-60° C. The reactionmass was stirred for 20 min at 55-60° C., cooled to 25-30° C. andheptane (50 ml) was added. The reaction mass was stirred for 30 min at55-60° C., cooled to 25-30° C. and stirred for 15 hrs at the sametemperature. The solid obtained was filtered, washed with ethanol (10ml) and suck dried for 30 min. To the resulting wet solid (HPLC purity:99.48%, alpha isomer content: 0.126%) ethanol (75 ml) was added at25-30° C., the reaction mass was raised to reflux and stirred for 10 minat reflux. The reaction mass was further cooled to 25-30° C. and stirredfor 3 hrs at 25-30° C. The resulting solid was filtered, washed withethanol (5 ml) and dried under vacuum at 75-80° C. for 5 hrs to obtainCanagliflozin DL-pipecolic acid co-crystal (2.5 gms).

HPLC purity: 99.88%, Alpha isomer content by HPLC: <0.05%, The PXRD isset forth in FIG. 01, The ¹H NMR is set forth in FIG. 02, The DSCthermogram is set forth in FIG. 03, The TGA is set forth in FIG. 04, TheIR is set forth in FIG. 05.

Example 3: Preparation of Canagliflozin DL-pipecolic Acid Co-Crystal:(ethanol+ethyl acetate)

To a round bottom flask equipped with reflux condenser, ethanol (10 ml)and ethyl acetate (50 ml) was added followed by canagliflozin (5 gm) andstirred for 10 min at 25-30° C. DL-Pipecolic acid (1.74 gm) was added;the contents were heated to reflux and stirred for 30 min. Then thereaction mass was cooled to 25-30° C. and the solid was filtered. Thewet solid thus obtained was added into the mixture of ethanol (10 ml)and ethyl acetate (50 ml) and heated to reflux. The reaction mass wasfurther allowed to cool to 25-30° C. and the solids were filtered to getCanagliflozin DL-pipecolic acid co-crystal (4 gms). HPLC purity: 99.5%.

Example 4: Preparation of Canagliflozin L-pipecolic Acid Co-Crystal:(ethanol+heptane)

To a round bottom flask equipped with reflux condenser, ethanol (100ml), Canagliflozin (5 gms) and L-Pipecolic acid (1.74 gms) were addedand reaction mass was allowed to raise to 70-75° C. Cooled the reactionmass to 55-60° C. and heptane (50 ml) was added. The reaction mass wasfurther cooled to 25-30° C. and filtered the solid. The resulting wetsolid was recrystallized from ethanol (75 ml) to obtain CanagliflozinL-pipecolic acid co-crystal (3.5 gm).

Example 5: Preparation of Canagliflozin L-pipecolic Acid Co-Crystal:(ethanol+ethyl acetate)

To a round bottom flask equipped with reflux condenser, Canagliflozin (5gm), ethanol (10 ml) and ethyl acetate (50 ml) were added and thereaction mass was stirred for 10 min at 25-30° C. L-Pipecolic acid (1.74gm) was added, the reaction mass was allowed to rise to reflux andstirred for 30 min. Then the reaction mass was cooled to 25-30° C. andthe solid was filtered. To the resulting wet solid, ethanol (10 ml) andethyl acetate (50 ml) was added and raised the temperature of thereaction mass to reflux. The reaction mass was further cooled to 25-30°C. and the solids were filtered to get Canagliflozin L-pipecolic acidco-crystal (3.5 gms).

Example 6: Preparation of Canagliflozin D-pipecolic Acid Co-Crystal:(ethanol+heptane)

To a round bottom flask equipped with reflux condenser, ethanol (100ml), Canagliflozin (5 gms) and D-Pipecolic acid (1.74 gms) were addedand the reaction mass was heated to 70-75° C. The contents of the flaskwere allowed to cool to 55-60° C. and added heptane (50 ml). Cooled thereaction mass further to 25-30° C. and the solid was filtered. Theresulting wet solid was recrystallized from ethanol (75 ml) to obtainCanagliflozin D-pipecolic acid co-crystal (3.5 gm).

Example 7: Preparation of Canagliflozin D-pipecolic Acid Co-Crystal:(ethanol+ethyl acetate)

To a round bottom flask equipped with reflux condenser, Canagliflozin (5gm), ethanol (10 ml) and ethyl acetate (50 ml) were added and stirredthe contents for 10 min at 25-30° C. D-Pipecolic acid (1.74 gm) wasadded, heated the contents to reflux temperature and stirred for 30 min.Then, the reaction mass was cooled to 25-30° C. and the solid wasfiltered. The resulting wet solid was charged into the mixture ofethanol (10 ml) and ethyl acetate (50 ml), heated to reflux, cooled to25-30° C. and the solids were filtered to get Canagliflozin D-pipecolicacid co-crystal (3.5 gms).

Example 8: Preparation of Canagliflozin Nicotinic Acid Co-Crystal

To a round bottom flask equipped with reflux condenser, Canagliflozin (2gms), ethanol (40 ml), and nicotinic acid (0.6 gm) was added at 25-30°C. Heated the contents of the flask to 70-75° C. and allowed to cool to25-30° C. The reaction mass was stirred for 5 hrs at 25-30° C. andfiltered the solid to obtain Canagliflozin Nicotinic acid co-crystal(0.3 gm).

Example 9: Preparation of Canagliflozin pyrazine-2-carboxylic AcidCo-Crystal

To a round bottom flask equipped with reflux condenser, Canagliflozin (2gms) was dissolved in ethanol (40 ml), and added pyrazine-2-carboxylicacid (0.6 gm) at 25-30° C. Heat the contents to 70-75° C. and allowed tocool to 25-30° C. The reaction mass was stirred for 5 hrs at 25-30° C.and filtered the solid to obtain Canagliflozin pyrazine-2-carboxylicacid co-crystal (0.4 gm).

Example 10: Preparation of Canagliflozin Pyrazole Co-Crystal

To a round bottom flask equipped with reflux condenser, ethanol (100ml), Canagliflozin (5 gms) and pyrazole (0.8 gms) were added and thereaction mass was heated to 70-75° C. The contents of the flask wereallowed to cool to 55-60° C. and added heptane (50 ml). Cooled thereaction mass further to 25-30° C. and the solid was filtered. Theresulting wet solid was purified from mixture of ethanol (75 ml) andn-heptane (75 ml) to obtain Canagliflozin pyrazole co-crystal co-crystal(4 gm).

Example 11: Preparation of Canagliflozin

To a round bottom flask equipped with reflux condenser, ethyl acetate(30 ml) and Canagliflozin DL-pipecolic acid co-crystal (5 gms) was addedat 25-30° C. Sodium bicarbonate solution (2.5 gm dissolved in 50 mlwater) was added to the reaction mass at 25-30° C. and stirred for 30min at the same temperature. The resulting organic layer was washed withwater and solvent from the organic layer was distilled completely undervacuum at below 45° C. Cyclohexane (30 ml) was added to the resultingresidue at 25-30° C., stirred for 30 min at 25-30° C., filtered thesolid and washed with cyclohexane (5 ml). The obtained solids are driedunder vacuum at below 45° C. for 10.0 hrs to obtain amorphouscanagliflozin (3.0 gms). HPLC purity: 99.8%.

Alpha isomer content by HPLC: <0.05%, The PXRD is set forth in FIG. 06,The TGA is set forth in FIG. 07, The IR is set forth in FIG. 08.

Example 12: Preparation of Canagliflozin

To a round bottom flask equipped with reflux condenser, ethyl acetate(50 ml), Canagliflozin (5 g), methanol (2.5 ml) and diethyl ether (5 ml)were added and allowed to cool to 0-5° C. Ammonia gas was purged for 20min at 0-5° C., filtered the resulting solids and washed with diethylether (10 ml). The obtained solid was dissolved in ethyl acetate (40 ml)at 25-30° C. and washed with water. The resulting organic layer wasdistilled out completely under vacuum at below 50° C. Cyclohexane (25ml) was added to the resultant compound and stirred for 30 min at 25-30°C. The obtained solid was filtered, washed with cyclohexane (5 ml) anddried under vacuum at below 45° C. for 10 hrs to obtain amorphouscanagliflozin (1 gm).

HPLC purity: 99.0%.

Example 13: Preparation of Dapagliflozin DL-pipecolic Acid Co-Crystals

To a round bottom flask equipped with reflux condenser, dapagliflozin (5gms), isopropyl acetate (100 ml) and DL-pipecolic acid (1.5 gms) wereadded at room temperature and stirred the contents for 4 hrs at roomtemperature. The solid obtained was filtered, washed with isopropylacetate (10 ml) and suck dried for 20 min. The resulting solid was driedunder vacuum for 16 hrs at room temperature and further dried undervacuum for 7 hrs at 40° C. to obtain dapagliflozin DL-pipecolic acidco-crystals (4.7 gms).

The PXRD is set forth in FIG. 09, The ¹H NMR is set forth in FIG. 10,The DSC thermogram is set forth in FIG. 11, The TGA is set forth in FIG.12.

Example 14: Preparation of Dapagliflozin DL-pipecolic Acid Co-Crystals

To a round bottom flask equipped with reflux condenser, isopropylacetate (20 ml) and DL-pipecolic acid (631 mg) were added at 20-25 C°and the reaction mixture was stirred for 10 mins. Dapagliflozin (2.0 gm)was added to the reaction mixture at 25-30° C. and stirred the contentsfor 24 hrs at 20-25° C. The solid obtained was filtered and washed withisopropyl acetate (5 ml). The obtained solid was dried under vacuum at40-45° C. for 20 hrs to obtain dapagliflozin DL-pipecolic acidco-crystals (2.3 gms).

Example 15: Preparation of Dapagliflozin D-pipecolic Acid Co-Crystals

To a round bottom flask equipped with reflux condenser, isopropylacetate (10 ml) and D-pipecolic acid (315 mg) were added at 20-25 C° andthe reaction mixture was stirred for 10 mins. Dapagliflozin (1.0 gm) wasadded to the reaction mixture at 25-30° C. and stirred the contents for24 hrs at 20-25° C. The solid obtained was filtered and washed withisopropyl acetate (3 ml). The obtained solid was dried under vacuum at40-45° C. for 20 hrs to obtain dapagliflozin D-pipecolic acidco-crystals (1.2 gms).

The PXRD is set forth in FIG. 13.

Example 16: Preparation of Dapagliflozin L-pipecolic Acid Co-Crystals

To a round bottom flask equipped with reflux condenser, isopropylacetate (10 ml) and L-pipecolic acid (315 mg) were added at 20-25 C° andthe reaction mixture was stirred for 10 mins. Dapagliflozin (1.0 gm) wasadded to the reaction mixture at 25-30° C. and stirred the contents for24 hrs at 20-25° C. The solid obtained was filtered and washed withisopropyl acetate (3 ml). The obtained solid was dried under vacuum at40-45° C. for 20 hrs to obtain dapagliflozin L-pipecolic acidco-crystals (1.1 gms).

The PXRD is set forth in FIG. 14.

Example 17: Preparation of Dapagliflozin 2,3-butanediol Solvate(MTBE-heptane)

To a round bottom flask equipped with reflux condenser, dapagliflozin(0.5 gms) and MTBE (3 ml) were added at 20-25° C. and stirred thereaction mixture at 20-25° C. for 10 mins. 2,3-butanediol (110 mgs) wasadded and stirred the reaction mixture for 1 hr at 20-25° C. followed byheptane (1 mL) was added. Stirred the reaction mixture for 30 mins at20-25° C., seed crystals of dapagliflozin 2,3-butanediol solvate (˜20mg) was added and stirred for 15 mins at 20-25° C. Heptane (9 mL) wasadded and stirred for 2 hrs at 20-25° C. The resulting solids wasfiltered under vacuum at 20-25° C., washed with heptane (3 mL), suckdried for 10 mins and finally dried at room temperature under vacuum for24 hrs to obtain dapagliflozin 2,3-butanediol solvate (570 mg).

The PXRD is set forth in FIG. 15, The ¹H NMR is set forth in FIG. 16,The DSC thermogram is set forth in FIG. 17, The TGA is set forth in FIG.18.

Example 18: Preparation of Dapagliflozin 2,3-butanediol Solvate(isopropyl acetate-heptane)

To a round bottom flask equipped with reflux condenser, dapagliflozin(0.5 gms) and isopropyl acetate (2 ml) were added at 20-25° C. andstirred the reaction mixture at 20-25° C. for 10 mins. 2,3-butanediol(110 mgs) was added and stirred the reaction mixture for 1 hr at 20-25°C. followed heptane (1 ml) was added. Stirred the reaction mixture for30 mins at 20-25° C., seed crystals of dapagliflozin 2,3-butanediolsolvate (˜20 mg) was added and stirred for 15 mins at 20-25° C. Heptane(9 ml) was added and stirred for 2 hrs at 20-25° C. The resulting solidwas filtered under vacuum at 20-25° C., washed with heptane (3 mL), suckdried for 10 mins and finally dried at room temperature under vacuum for24 hrs to obtain dapagliflozin 2,3-butanediol solvate (620 mg).

Example 19: Preparation of Amorphous Dapagliflozin (Methanol-water)

To a round bottom flask equipped with reflux condenser, dapagliflozin (5gms) and methanol (15 ml) were added. The reaction mixture was heated to60° C., stirred for 10 mins at 60° C. to obtain clear solution and thenallowed to cool to 5° C. To the resulting solution, first portion ofwater (13.5 ml) was added, seeded with amorphous dapagliflozin (˜30 mg)and stirred for 30 mins at 0-5° C. To the resulting reaction mixtureremaining water was added in multiple lots (3 lots, 40 ml for each lot)with stirring for 30 mins at 0-5° C. after each addition and finallystirring for 2 hrs at 0-5° C. The resulting solid was filtered andwashed with water (100 ml). The resulting solid was suck dried for 2 hrsunder vacuum and further dried at 35° C. for 24 hrs to obtain amorphousdapagliflozin (4.5 gms).

The PXRD is set forth in FIG. 19, The DSC thermogram is set forth inFIG. 20.

Example 20: Preparation of Amorphous Dapagliflozin (methanol-water)

To a round bottom flask equipped with reflux condenser, dapagliflozinDL-pipecolic acid co-crystals (1 gm) and water (10 ml) were added atroom temperature and the reaction mixture was stirred for 5 mins. 1Nsodium hydroxide (1 ml) was added and the reaction mixture was stirredfor 5 mins at room temperature. Methanol (5 ml) was added and thereaction mixture was heated to 60° C., stirred for 10 mins at 60° C. toobtain clear solution and allowed to cool to 5° C. To the resultingsolution, first portion of water (4 ml) was added, seeded with amorphousdapagliflozin (˜10 mg) and stirred for 30 mins at 0-5° C. To theresulting reaction mixture, remaining water was added in multiple lots(3 lots, 10 ml for each lot) with stirring for 30 mins at 0-5° C. aftereach addition and finally stirring for 2 hrs at 0-5° C. The resultingsolid was filtered and washed with water (10 ml). The resulting solidwas suck dried for 2 hrs under vacuum and further dried at 35° C. for 24hrs to obtain amorphous dapagliflozin (0.85 gms).

Example 21: Preparation of Amorphous Dapagliflozin (MTBE-Heptane)

To a round bottom flask equipped with reflux condenser, dapagliflozin (2gms) and MTBE (16 ml) were added. The reaction mass was heated to 55° C.and stirred for 15 mins at 55° C. The resulting solution was added dropwise to pre-cooled heptane (96 ml) at 15° C. The reaction mixture wasstirred for 30 mins at 15° C., filtered the solids and washed withheptane (10 ml). The resulting solid was dried at 35° C. under vacuumfor 16 hrs and at 55° C. under vacuum for 12 hrs to obtain amorphousdapagliflozin (1.9 gms).

Example 22: Preparation of Amorphous Dapagliflozin (MTBE-Cyclohexane)

To a round bottom flask equipped with reflux condenser, dapagliflozin (2gms) and MTBE (16 ml) were added. The reaction mixture was heated to 55°C. and stirred for 15 mins at 55° C. The resulting reaction mixture wasadded drop wise to pre-cooled cyclohexane (96 ml) at 15° C. The reactionmixture was stirred at 15° C. for 30 mins, filtered and washed withcyclohexane (10 ml). The resulting solid was dried at 35° C. undervacuum for 16 hrs and further dried at 55° C. under vacuum for 12 hrs toget amorphous dapagliflozin (1.85 gms).

Example 23: Preparation of Amorphous Dapagliflozin (MTBE-Heptane)

To a round bottom flask equipped with reflux condenser, dapagliflozinDL-pipecolic acid co-crystals (2 gms) and ethyl acetate (30 mL) wereadded and stirred the reaction mixture for 5 mins at room temperature.Water (30 mL) was added and stirred the mixture for 5 mins at roomtemperature. 1N Sodium hydroxide solution (3.7 ml) was added to thereaction mixture and the mixture was stirred at room temperature for 10mins. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate (20 ml). The combined organic layer waswashed with water (20 ml) and evaporated completely at 50° C. Theobtained residue was co-distilled with heptane (20 ml) under vacuum at50° C. The resulting residue was dissolved in MTBE (6.5 mL) at roomtemperature and heptane (26 mL) was added at 15° C. The reaction mixturewas stirred at 15° C. for 30 mins, filtered the solids and dried at 35°C. for 16 hrs and further dried at 55° C. under vacuum for 12 hrs toobtain amorphous dapagliflozin (980 mg).

Example 24: Preparation of Amorphous Dapagliflozin (methyl acetate)

To a round bottom flask equipped with reflux condenser, dapagliflozinDL-pipecolic acid co-crystals (1 gm) and water (10 ml) were charged atroom temperature and stirred the reaction mixture for 5 mins. 1N sodiumhydroxide (1 ml) was added and stirred the reaction mixture for 5 minsat room temperature. Methyl acetate (10 ml) was added to the reactionmixture, stirred the solution for 10 mins at room temperature and theobtained layers were separated. The aqueous layer was extracted withmethyl acetate (10 ml) and the combined organic layers were washed withwater (10 ml). The organic layer was distilled at 50° C. under vacuum toobtain amorphous dapagliflozin (0.4 gms).

Example 25: Preparation of Amorphous Dapagliflozin (Methyl tertiarybutyl ether)

To a round bottom flask equipped with reflux condenser, dapagliflozinDL-pipecolic acid co-crystals (1 gm) and water (10 ml) were added atroom temperature and the reaction mixture was stirred for 5 mins. 1Nsodium hydroxide (1 ml) was added and the reaction mixture was stirredfor 5 mins at room temperature. Methyl tertiary butyl ether (10 mL) wasadded to the reaction mixture, stirred the solution for 10 mins at roomtemperature and the obtained layers were separated. The aqueous layerwas extracted with methyl tertiary butyl ether (10 ml) and the combinedorganic layers were washed with water (10 mL). The organic layer wasdistilled at 50° C. under vacuum to obtain amorphous dapagliflozin (0.8gms).

Example 26: Preparation of Amorphous Dapagliflozin (Isopropyl Acetate)

To a round bottom flask equipped with reflux condenser, dapagliflozinDL-pipecolic acid co-crystals (1 gm) and water (10 ml) were charged atroom temperature and stirred the reaction mixture for 5 mins. 1N sodiumhydroxide (1 ml) was added and the reaction mixture was stirred for 5mins at room temperature. Isopropyl acetate (10 ml) was added to thereaction mixture, stirred the solution for 10 mins at room temperatureand the obtained layers were separated. The aqueous layer was extractedwith Isopropyl acetate (10 ml) and the combined organic layers werewashed with water (10 ml). The organic layer was distilled at 50° C.under vacuum to obtain amorphous dapagliflozin (0.8 gms).

Example 27: Preparation of Amorphous Dapagliflozin (Methanol-water)

To a round bottom flask equipped with reflux condenser, dapagliflozin (4gms) and methanol (12 ml) were added. The reaction mixture was heated to60° C., stirred for 10 mins at 60° C. to obtain clear solution andcooled to room temperature. To the resulting solution, water (100 ml)was added at room temperature. The reaction mixture was stirred at roomtemperature for 10 mins, cooled to 0-5° C. and stirred for 6 hrs. Theresulting solid was filtered and washed with chilled water (20 ml). Theresulting solid was dried at room temperature under vacuum for 5 hrs andfurther dried at 40° C. under vacuum for 6 hrs to obtain amorphousdapagliflozin (3.0 gms).

Example 28: Preparation of Amorphous Dapagliflozin (Methanol-water)

To a round bottom flask equipped with reflux condenser, dapagliflozin (4gms) and methanol (12 ml) were added. The reaction mixture was heated to60° C., stirred for 10 mins at 60° C. and cooled to room temperature.The resulting solution was added drop wise to pre-cooled water (125 ml)at 0-5° C. The mixture was stirred at 0-5° C. for 6 hrs, filtered thesolid and washed with chilled water (25 ml). The resulting solid wasdried at 30-35° C. under vacuum for 16 hrs and further at 50-55° C.under vacuum for 12 hrs to obtain amorphous dapagliflozin (3.0 gms).

Example 29: Preparation of Empagliflozin DL-pipecolic Acid Co-Crystals

To a round bottom flask equipped with reflux condenser, Empagliflozin(10 gm), DL-pipecolic acid (5.75 gm) and n-butanol (100 ml) were addedand raised the temperature to 80° C. DM water (5 ml) was added andstirred the reaction mass for 30 min. The resulted clear solution wasallowed to cool to 25° C. and stirred for 30 min. The suspension wasfurther allowed to cool to 3° C., filtered the product and washed withn-butanol (20 ml). The obtained solid was dried under vacuum for 8 hrsat 40° C. to obtain empagliflozin DL-pipecolic acid co-crystals (12.8gms).

The PXRD is set forth in FIG. 21, The ¹H NMR is set forth in FIG. 22,The DSC thermogram is set forth in FIG. 23, The TGA is set forth in FIG.24.

Example 30: Preparation of Empagliflozin DL-pipecolic Acid Co-Crystals

To a round bottom flask equipped with reflux condenser, Empagliflozin (1gm), pipecolic acid (0.572 gm) and n-butanol (10 ml) were added andraised the temperature to 80° C. DM water (0.5 ml) was added and stirredthe reaction mass for 30 min. The resulted clear solution was cooled to25° C. and stirred the suspension for 30 min. The suspension was furthercooled to 3° C., washed with n-butanol (2 ml) and suck dried for 30 min.The obtained solid was dried under vacuum for 8 hrs at 45° C. to obtainempagliflozin DL-pipecolic acid co-crystals (1.1 gms).

It will be understood that various modifications may be made to theembodiments disclosed herein. Therefore, the above description shouldnot be construed as limiting, but merely as exemplifications ofpreferred embodiments. For example, the functions described above andimplemented as the best mode for operating the present invention are forillustration purposes only. Other arrangements and methods may beimplemented by those skilled in the art without departing from the scopeand spirit of this invention. Moreover, those skilled in the art willenvision other modifications within the scope and spirit of thespecification appended hereto.

The invention claimed is:
 1. A process for the preparation ofempagliflozin DL-pipecolic acid co-crystals, comprising: a) providing asolution or suspension comprising empagliflozin and DL-pipecolic acid inone or more solvents; and b) isolating the empagliflozin DL-pipecolicacid co-crystals.
 2. The process of claim 1, wherein the solvents areselected from the group consisting of an ester, an alcohol, an ether, aketone, an aliphatic hydrocarbon, a halogenated hydrocarbon, a nitrile,water, and mixtures thereof.
 3. The process of claim 2, wherein thesolvent is one or more of n-butanol, ethanol and acetone.